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Studies of chronic alcohol abusers during detoxification

The time of the planned admission for the assay of alcohol levels, biochemical parameters as well as haematological indices. Heparinised blood specimens were taken both at the time of admission and 7 days after detoxification for the analysis of taurine and plasma amino acids. Information on both the maximal daily dose and total dose of chlordiazepoxide administered during the alcohol detoxification stage was also collected. In approximately one third of these patients, n 10, acamprosate, 666 mg x 3 x day was administered during this detoxification period. In these patients the levels of acamprosate in the plasma after 7 days of administration was assayed by gas chromatography mass spectrometry7. For the analysis of the data, the patients were divided into three groups according to whether 1. Glutamic acid increased after 7 days of detoxification 2. Glutamic acid decreased after 7 days of detoxification and 3. The patients had received acamprosate during the seven days of...

Improving the compound selection and optimization process

Fects, such as transcriptional induction of detoxification or drug efflux systems. For instance, studies investigating the effect of triclosan on M. tuberculosis exhibit a striking upregulation of such bacterial defense systems 31 . Similarly, various antibacterial agents with aromatic character induce mycobacterial genes most likely involved in drug efflux and in detoxification such as monooxygenase, dioxygenase and methylase genes. Thus, expression profiling can aid in a systematic prioritization of screening hit compounds by focusing on the molecules showing no or little indications of drug resistance in their transcriptional response.

Resistance to Platinum Drugs

Furthermore, quite a number of additional mechanism of platinum drug resistance have been described. These mechanisms include an increased capacity for platinum-DNA adduct tolerance (Parker et al. 1991 Mamenta et al. 1994), detoxification by metallothioneins (Kelley et al. 1988), or alterations in regulatory proteins, e.g. in the oncogene encoded factor c-fos (Scan-lon et al. 1991).

Other Drugs And Depression

Use of sedatives, including benzodiazepines, has been linked to depression (187,188), although few empirical studies of this relationship exist (189). A positive correlation between prewithdrawal depressive symptoms and sedative-withdrawal symptom severity has been reported (190), as has the presence of depressive symptoms in withdrawal as a predictor of withdrawal failure (191). In a prospective study involving 82 alcohol- or benzodiazepine-dependent subjects undergoing detoxification, Charney et al. (192) found that the benzodiazepine-dependent subjects had a worse outcome in terms of abstinence at 3 months but not at 6 months.

Results And Discussion

After an irradiation time of 10 min the effect of hypotaurine was high and cell viability allowed measurement of enzymatic activities, recorded 24 h after treatment on the cytosol of cultured cells. Ratios of specific activities of some detoxifying enzymes are reported in Table 4. Absolute activity values are not shown. It is well known that GSH Px is responsible for the detoxification of hydrogen peroxide and organic hydroperoxides. Its activity increases in those conditions where peroxide concentration increases in cells. Hypotaurine reacts very slowly6 with H2O2 and is not a valuable candidate for peroxide scavenging. In conclusion, in cells treated with methylene blue + light the activation of enzymatic defences is not sufficient to counteract ROS attack and we observe cell death. In hypotaurine treated cells viability is higher respect to the control and this would indicate that the enzymatic scavenging activation is not necessary for cell surviving. The protective effect of...

Historical Perspective

For many years it has been assumed that the majority of toxins which cause coma in hepatic failure are small dialyzable molecules. As a result, most liver support systems and therapeutic regimens relied primarily on blood detoxification. However, the pathogenesis of acute liver failure is complex and many investigators, including ourselves, have argued that isolated viable hepatocytes should be used to construct a liver support system to provide not only detoxification, but also missing liver synthetic functions. This suggests that a clear distinction should be made between systems designed to strictly purify patient blood from toxins and devices incorporating liver tissue preparations to carry out detoxification and provide synthetic function. The former are based on the artificial kidney principle a classic example is hemodialysis, which was first applied by Kiley et al, and hemoperfusion, which was first tried by Schechter et al using cationic resins and several years later by...

Primary Test Systems In Vitro Metabolic Activation

It should be noted that this system is only a first approximation to the complex metabolic processes that occur in vivo, and in particular there is little account taken of the phase II detoxification reactions. Such factors should be considered when interpreting positive in vitro results which are only seen in the presence of S9 mix.

Expert Computer Systems for Predicting Genotoxicity

Many structural factors affect the mutagenicity and carcinogenicity of chemicals, including (1) the intrinsic reactivity (electrophilicity) (2) the electron density in and near reactive centres (3) substituent effects, e.g. steric hindrance (4) susceptibility to metabolic activation and detoxification (5) the stability of reactive forms of chemicals (6) the ability of chemicals and their metabolites to traverse biological membranes (7) the size and shape of molecules which control access to target sites on DNA (8) the type and conformation of adducts formed between the chemical and DNA and (9) the susceptibility of the adduct to DNA repair. Ideally, expert systems should take all of these factors into account when assessing the activities of mutagens and carcinogens.

Endogenous Antigenotoxins

Evidence is increasing that DNA damage can occur as a result of normal cellular functions. There are three main sources of DNA damage. (1) many cellular processes require or consume oxygen. Sometimes oxygen and other small molecules such as hydroxyl (OH) groups become electron deficient and may escape normal cellular pathways such as those of the respiratory chain, and these oxygen radicals can react with DNA and may cause mutations or cancer. (2) A second very important source of oxygen radicals in the body is the normal burst of free radicals generated by neutrophils, in order to kill bacteria, viruses, etc., entering the body, as part of the normal defence against such intruders. (3) In the normal metabolism of endogenous or exogenous molecules, often very reactive metabolites are formed intracellular by cytochrome P450-mediated reactions. Sometimes such metabolites may be mutagenic or carcinogenic and need to be further metabolized or detoxified by appropriate endogenous systems....

Mechanisms By Which Antigenotoxins May

A large number of antigenotoxic and anticarcinogenic agents have been detected, some of which have proved effective in clinical trials. The multistage nature of carci-nogenesis offers the possibility for intervention at each stage of the process, as shown in Figure 3. At the initiation stage chemoprevention can be accomplished by inhibition of metabolic activating enzymes or the enhancement of detoxification enzymes, radical scavengers and binding

Liver Support Unit Logistics

The second, equally important, component of an LSU is a team of researchers who are part of the program. This group should include hepatic physiologists, experimental surgeons, neurophysiologists, molecular physiologists, molecular pathologists, cell culture experts, detoxification cytochrome P-450 experts, tissue and materials engineers, immu-nologists, analytical chemists and others. In spite of a massive body of literature on the pathophysiology of SALF, many important issues remain unresolved. The LSU provides an opportunity to use clinical observations as a starting point for meaningful basic scientific investigation. There has to be close interaction between clinicians and basic scientists to carry out well-designed clinical studies using sophisticated basic laboratory tools and to initiate laboratory projects to answer clinically relevant questions.

The Role Of Oxidative Stress In Aging

Asecond focus of aging in the CNS is oxidative stress and the mitochondrion. Reactive oxygen species (ROS) are oxidants that, if unrestricted, can cause oxidative damage to the mitochondria, cellular proteins, lipids, and nucleic acids. ROS are the normal byproducts of cellular metabolism in the mitochondrion. Free radicals are chemical species with a single unpaired electron, which is highly reactive. The majority of free radicals that damage biological systems are oxygen radicals and other ROS, which are byproducts formed in the cells of aerobic organisms. The generation of mitochondrial ROS is a consequence of oxidative phosphorylation, a process that occurs in the inner mitochondrial membrane and one that involves the oxidation of NADH to produce energy. Under normal circumstances our natural antioxidant defense systems detoxify the superoxide anion by the mitochondrial manganese (Mn) superoxide dismutase

Squamous Cell Carcinoma

Transport of tobacco-associated carcinogens across the oesophageal lining. It may also impair the ability of the liver to detoxify carcinogens. In contrast, there appears to be a strong protective effect between the consumption of antioxidant vitamins and fresh fruits in areas at high risk for SCC.

Matrixrepresented protein networks genome maps

The resulting clustered map, shown in Figure 5b, reveals important characteristics of protein network connectivity and hierarchy. Many of the genes cluster into distinct modules, participating in related cellular functions 50 . Some of these modules correspond to protein pathways or complexes, while others contain genes that serve related cellular functions. Some of the functional modules are indicated in Figure 5b. Figure 5c depicts a zoomed-in region of the clustered map, indicated by the black square. Functional modules in this region correspond to genes involved in detoxification, polyketide synthesis, energy metabolism, and the degradation of fatty acids. This example illustrates how hierarchical clustering of genomic maps can enable the rapid identification of functional modules on a genome-wide basis 50 .

Frederick D Watanabe Elaine Kahaku Theodore Khalili Paul Ting Anthony Navarro Achilles A Demetriou

In spite of substantial advances in general supportive therapy and critical care, mortality in fulminant hepatic failure (FHF) remains unacceptably high, due primarily to incomplete understanding of the pathophysiology of the disease.1 Despite this, clinicians have attempted to develop rational novel therapeutic modalities focusing mostly on plasma detoxification.2-7 Whole liver perfusion using either human or xenogeneic organs has been used successfully to treat patients with FHF, but is limited by lack of human livers and logistical considerations in the case of animal organ use.8-9 In previous sections of this monograph we presented the rationale for using intact isolated cryopreserved hepatocytes to develop a bioartificial liver (BAL). Several investigators have developed and tested a variety of hepatocyte-based systems.10-15 We have developed a BAL containing porcine hepatocytes and have demonstrated its ability to provide detoxifying and synthetic functions in a series of in...

Parallels in the feeding ecology

Perhaps not by coincidence, a baboon was chosen as donor in the first attempt to transplant an animal liver into a human. The surgeons at the University of Pittsburgh Medical Center (where the operation was performed on June 28, 1992) apparently judged the baboon liver to be the most compatible replacement. From an evolutionary point of view this choice should come as no surprise. The limiting factor in any feeding adaptation is not only the ability to acquire and digest a certain configuration of staple ingredients but also, if not more so, the ability to remove typical toxins and harmful substances - the primary responsibility of the liver. As part of the digestive system, the liver processes products of digestion carried from the gut (through the portal vein). Its main function is to metabolize, store, and detoxify nutrients, as well as to

Hepatobiliary Tree 1231 Pathophysiology 12311 Normal Anatomy and Physiology

Liver function is diverse and includes the synthesis of enzymes albumin, coagulation proteins, urea and steroids (such as cholesterol and primary bile acids) the conjugation of bilirubin,the detoxification of drugs and storage of fat-soluble vitamins. Hepato-cytes are also responsible for gluconeogenesis and glycolysis. The Kupffer cells, which engage in phagocytosis and secrete cytokines, play a role in immune regulation.

Metabolism Of Chemical Carcinogens

There are a number of these metabolic pathways that together are part of a more extensive defence system, the overall role of which is ideally to process and detoxify noxious chemicals. Enzyme-catalysed and diverse in nature, these reactions have been defined and split into what are called phase I and phase II metabolism (Williams, 1971). Phase I can be separated into oxidation, reduction and hydrolytic reactions and phase II comprises a series of conjugation reactions in which a polar endogenous group is added to the xenobiotic chemical. The overall effect of this biochemistry is to convert xenobiotics, which are often lipophilic molecules, into more polar water-soluble and therefore more readily excreted products. Generally, phase I reactions unmask or introduce a functional group into the molecule and phase II metabolism conjugates the derivative with a polar water-soluble endogenous molecule, that is often acidic in nature. However, it is these same pathways of detoxification...

Basis for Sports Nutrition Interest

There is relatively little reason for molybdenum to be of interest to physically active people. Molybdenum is a transition element that readily changes its oxidation state and can thus act as an electron transfer agent in oxidation-reduction reactions in which it cycles from Mo6+ to reduced states. This is the basis for molybdoenzymes' catalyzing the hydroxylation of various substrates using oxygen from water. Molybdenum hydroxylases may be important in metabolizing drugs and foreign compounds that enter the body.96 Thus, low dietary molybdenum might be detrimental to an athlete's health through an inability to effectively detoxify some xenobiotic compounds.

Exogenous Antigenotoxins

Aflatoxin Biosynthesis Pathway

Most antigenotoxins are taken up via consumption of food, and more especially from fruit and vegetables as part of the diet. Recently however, synthetic antigenotoxins such as nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin, sulindac and oltipraz have been recognized. Also food supplements in the form of tablets containing vitamins, minerals, trace elements and other additives can be included in this group. NSAIDs have been shown to prevent the growth and formation of colon adenomas or carcinomas in several epidemiological and intervention studies. The mechanism of this protective effect may be very complex and multifactorial but enhancement of detoxification enzymes by NSAIDs was evident. Oltipraz, which is both an inhibitor of activating systems and an enhancer of detoxification enzymes, was shown to have strong antigenotoxic potential by preventing aflatoxin Brinduced DNA damage (Figure 1). Aflatoxin B1 is a fungal toxin, thought to be the cause of many...

Mechanisms Of Tumour Induction

The mechanisms by which tobacco causes cancer can best be illustrated by considering the relationship between cigarette smoking and lung cancer, because it is here that the most information is available. The overall framework for discussing this information is illustrated in Figure 4 (Hecht, 1999). Carcinogens form the link between nicotine addiction and cancer. Nicotine addiction is the reason why people continue to smoke. While nicotine itself is not considered to be carcinogenic, each cigarette contains a mixture of carcinogens, including a small dose of PAHs and NNK among other lung carcinogens, tumour promoters and co-carcinogens (Hecht, 1999). Carcinogens such as NNK and PAHs require metabolic activation, that is, they must be enzymatically transformed by the host into reactive intermediates, in order to exert their carcinogenic effects. There are competing detoxification pathways which result in harmless excretion of the carcinogen. The balance between metabolic activation and...

Metabolic Functions Of Selenium

In humans who have a hereditary lack of GSHPx in erythrocytes, the ability of the erythrocytes to withstand stress induced by oxidizing agents is impaired and results in a hemolytic crisis.21 Glutathione peroxidase and PLGSHPx are major enzyme systems responsible for detoxification of H202 and lipid hydroperoxides. Lack of sufficient quantities of these enzymes from a Se deficiency, as well as from genetic defects or the inability to incorporate dietary Se into GSHPx, leads to signs and symptoms associated with peroxidative tissue damage.

Preoperative Assessment of Liver Function

Preoperative Lab Testing Form

Protide synthesis is altered with albumin level reduction, alteration of coagulation factors and a fall in immunoglobulins. The effects of obstruction extend to detoxification activity of the liver with decreased excretion of the substances metabolised in the liver. The systemic effects of biliary obstruction are evident with regard to cardiovascular activity, renal function, and the coagulation process. Jaundiced patients are more susceptible to developing postoperative shock consequent to depression of left ventricular activity and decreased peripheral vascular resistance as well as plasmatic volume. Renal function is impaired by hyperbilirubinemia, due to the reduction of renal perfusion related to cardiac pump impairment and to renal causes themselves, as natriuretic effects of bile salts and direct parenchymal toxicity of endotoxaemia renal failure in jaundice patients has a mortality that can reach 70 1 . Deprivation of bile at the intestinal level interferes with vitamin K...

Functions Of Chaperonins

There is some indication that the chaperonins may also play extracellular roles in animals. It is claimed that the early pregnancy factor, a protein detected by bioassay in the maternal serum of mammals within 24 h of fertilization, is identical to mitochondrial cpnlO (Cavanagh and Morton, 1994). However, there has been no report of the detection of cpnlO in serum by chemical methods, perhaps because the concentration of cpnlO may be very low. One of the cpn60 proteins from mycobacteria stimulates cytokine secretion by human monocytes, whereas cpnlO from Mycobacterium tuberculosis induces apoptosis in human T lymphocytes. These and related observations have been used to formulate the idea that the chaperonins are multiplex antigens i.e., they act simultaneously on a range of cell types in stress situations so that immune messages such as cytokines cause immune effector cells to adapt to cope with the stress (see Chapter 10). There are several reports that cpn60 occurs at sites outside...

Carcinogenblocking Activities Antimutagenicity

Inhibition of carcinogen uptake into cells, inhibition of carcinogen formation or activation, carcinogen deactiv-ation or detoxification, preventing carcinogen binding to DNA, and enhancing the level or fidelity of DNA repair are all carcinogen-blocking activities and potential chemo-preventive mechanisms (Wattenberg, 1978 Kelloff et al., 1995b). (See the chapter on Antigenotoxins and Cancer.) Deactivate detoxify carcinogen Enhancement of Carcinogen Deactivation Detoxification Enhancement of carcinogen deactivation detoxification is potentially a very important strategy for chemoprevention (De Flora and Ramel, 1998 Kelloff et al, 1995b). Two metabolic pathways are critical. The first is the introduction or exposure of polar groups (e.g. hydroxyl groups) on procarcinogens carcinogens via the phase I metabolic enzymes, which are primarily the microsomal mixed-function oxidases. These polar groups become substrates for conjugation. The second pathway is via the phase II metabolic enzymes...

Biological Effects Of Saffron And Its Components Studies In Vivo

There have been several recent investigations focusing on the effects of saffron and its components on the nervous system which have led to the discovery of an apparent interaction with ethanol. In one study, Zhang et al. (1994) examined the acute effects of saffron extract on passive-avoidance performance in normal and in learning- and memory-impaired mice. A single oral administration of extract had no effect on memory registration, consolidation or retrieval in normal mice. However, the extract did reduce the ethanol-induced impairment of memory registration in both step-through and step-down tests and the ethanol-induced impairment of memory retrieval in step-down tests. The extract also decreased the motor activity and prolonged the sleeping time induced by hexobarbital. The authors suggested that saffron ameliorates the impairment effects of ethanol on learning and memory processes, and possesses a sedative effect. They suggested four possible mechanisms for this effect 1)...

Influence of Genetic and Other Factors on Drug Effects in Cancers

Regarding cancer therapy, there are several known genetic alterations or factors markers that are expected to affect drug response. These include, drug transporter proteins, drug metabolizing enzymes that activate, inactivate, or detoxify drugs, and drug targets. The identification and understanding of these markers has the potential to allow clinicians to select appropriate therapy, and, therefore, avoid adverse drug reactions and therapeutic failures. Because of their important roles in drug pharmacokinetics and pharmaco-dynamics, genetic polymorphisms in phase I (oxidative) and phase II (con-jugative) enzymes are likely to represent some of the most common inheritable risk factors associated with common disease phenotypes, such as adverse drug reactions. Cytochrome P450 monoxigenases (CYPs) are phase I enzymes that catalyze the oxidation of endogenous and exogenous compounds, and are responsible for the metabolism of greater than 90 of clinically prescribed drugs (10). CYPs can...

Interpretation Of Results

Comparative trials have shown that false-positive and false-negative results in relation to cancer predictivity can be generated by each genotoxicity test. Experimental conditions such as the limited capacity of the in vitro metabolic activation system can lead to false-negative results in in vitro tests, whilst culture conditions such as changes in pH and high osmolality are known to cause false-positive results in in vitro mammalian assays. Guidelines for testing new chemical entities require a battery of tests measuring effects on a variety of genetic endpoints designed to detect the widest spectrum of gen-otoxins. This reduces the risk of false-negative results, whilst a positive result in any one in vitro assay does not necessarily mean that the chemical poses a genotoxic carcinogenic hazard to humans. Further investigation in relevant in vivo assays is required to put the results into perspective. The in vivo tests have advantages in terms of relevant metabolism, etc., and also...

Overview of Treatment

Detoxification Initial Intervention Stabilization and Detoxification Patients with comorbid anxiety disorders who have substance dependence should undergo treatment that addresses both disorders, as residual symptoms from one disorder may interfere with treatment of the other. For example, agoraphobia and other anxiety symptoms can impair the ability of patients to participate in treatment activities such as therapy groups or self-help groups. Since withdrawal can exacerbate anxiety symptoms, all patients with should undergo a supervised detoxification and any emergent withdrawal symptoms should be treated. Detoxification may be accomplished in an outpatient, inpatient, or residential setting depending on the drug used, the level of dependence, the severity of psychiatric problems, and the presence of coexist The proposed neurobiological mechanism for withdrawal is a change in the number of postsynaptic neurotransmitter receptors or in receptor sensitivity that occurs with chronic...

Antiproliferative Activity via Signal Transduction Pathways

Deactivation of steroids may prevent hormone-stimulated carcinogenesis. In this regard, aromatase inhibitors and modifiers of steroid hydroxylation have been described above under inhibition of carcinogen formation activation and carcinogen deactivation detoxification, respectively.

Markers Of Internal Dose The Example Of Haemoglobin And Dna Adducts

Enhanced activation, or inefficient detoxification, of carcinogens Enhanced activation, or inefficient detoxification, of carcinogens Figure 2 Many genes and environmental exposures contribute to the carcinogenic process. The effects can be additive or multiplicative, which are modifiable by interindividual variation in genetic function. It is proposed to include carcinogen metabolic activity and detoxification genes as caretaker genes involved in maintaining genomic integrity. (From Shields and Harris, 2000, Journal of Clinical Oncology, 18, 2309-2315.)

Gabriela Grigorescu and David Hunkeler Introduction

There have been numerous attempts to replace organ function using cell transplantation including direct injections of dissociated cells into organs such as the liver, kidney or spleen.1 5 Subcutaneous and intraperitoneal routes have also been evaluated.6 10 More recent investigations have applied extracellular matrix polymers as structural supports for cell transplantation and immunoprotection. , Potential medical applications of such artificial cells or tissue engineered organoids include an extracorporeal bioartificial liver for detoxification,2 artificial red blood substitutes,13 the extracorporeal artificial kidney for hemodialysis,14 immunosorbents15 and drug delivery systems.16 The transplantation of immunoisolated (microencapsulated) cells represents another emerging area in biotechnology research and commercialization. Under such a scenario, the encapsulated cells, which could be a xenograft, would be hidden from the immune system of the body, but would still be able to...

Sensory Receptors and Primary Neurons

In addition to bipolar receptor cells, the olfactory epithelium contains several other major cell types (see Fig. 7-1 (Figure Not Available) ). The sustentacular or supporting cells, whose apical ends have microvilli that extend into the olfactory mucus, span the distance from the epithelial surface to the basal laminae and function to (1) mechanically isolate the bipolar receptor cells from one another, (2) secrete mucopolysaccarides, (3) transport molecules across the epithelium, and (4) detoxify and degrade odorants. i Some of the basal cells, located near the basement membrane, serve as precursors for the generation of other cell types within the neuroepithelium. The duct cells of Bowman's glands line passages through which most of the olfactory mucus is secreted, whereas the microvillar cells, located at the surface of the epithelium, send tufts of microvilli into the nasal mucus. The function of these flask-shaped cells is unknown. However, they number about 600,000 in humans...

Predictive Toxicology and the Promise of Embryonic Stem Cells

The liver is the major organ for metabolism and transformation of xeno-biotics, where hepatocytes, the primary cells of the liver, perform core functions, including metabolism of diverse dietary molecules and chemicals and detoxification of compounds. Therefore, the availability of large numbers of human hepatocytes is a constant critical demand in toxicology and chemical risk assessment.21 Discarded livers which cannot be used for organ transplantation are the limited source for primary human hepatocytes, which in turn exhibit very limited in vitro proliferation ability.22 Initial progress has been achieved to generate hepatocyte-like cells from human embryonic stem cells following extensive research efforts.23,24 Recent studies revealed that differentiation of the endoderm, the liver precursor lineage, evolves from human embryonic stem cells in a more intricate manner than ectoderm and mesoderm lineages.25 For proper differentiation to ensue, an apparent epithelial-to-mesenchymal...


Of all the theoretic changes thought to contribute to encephalopathy, the most pervasive and long-standing is that of ammonia. Elevated levels of nitrogenous compounds were first associated with mental status changes in early experiments utilizing the Eck fistula (portocaval anastomosis) in dogs.4 In fact, the surgical bypass of hepatic detoxification results in elevated peripheral blood ammonia levels. Ammonia levels are frequently, but not consistently, elevated in humans with hepatic encephalopathy. Furthermore, the blood-brain barrier has an increased permeability for ammonia in patients with liver disease.5,6 PET scan studies using 13NH3 have shown an increased metabolism of ammonia in encephalopathic patients.6 The presence of ammonia in the brain has extensive theoretic consequences, as will be discussed below.1,7 The enzymatic machinery for the urea cycle is absent in the brain, which instead depends on glutamine synthesis. Ammonia has direct and indirect negative effects on...

What Are Herbicides

Glyphosate, or more precisely N-(phosphonomethyl) glycine, has been in use for more than 25 years. By inhibiting a specific enzyme, glyphosate blocks the synthesis of aromatic rings, present in the amino acids phenylalanine and tyrosine, plus a host of polyphenolic substances. This primary effect of glyphosate is not confined to plants. However, glyphosate does have the advantage of breaking down quickly in the soil to harmless products, including inorganic phosphate and glycine, the simplest amino acid. This breakdown is conducted by certain soil bacteria such as Salmonella typhimurium, which has now provided the gene for the enzyme that allows genetically engineered glyphosate-resistant plants to detoxify some of the glyphosate they are exposed to.22


Paternal toxicological screening could provide the means to intercede before repercussions originating from paternal exposures become apparent in the next generation. Because spermatogenesis is a process of continuous self-renewal, a transcriptome-based assay system such as a microarray provides the means to monitor and diagnose exposures, as well as provide a history of previous exposure. For example, collection of samples at regular intervals for 60 to 80 days (time to complete one round of spermatogenesis) and comparison of their RNA profiles to a normal fingerprint could be used to establish the type and severity of an exposure and subsequent detoxification. The value in our ability to identify, screen, and intercede is not limited to current environmental exposure. The significance and need to develop this capability are now reinforced by the threat of an unwarranted biological and chemical terrorist attack on the mass population. With this new diagnostic capacity we could ensure...

Human Studies

There is some evidence for reduced serotonergic function in alcoholism. Low concentrations of CSF 5-HIAA and 5-HT,71-73 decreased whole blood 5-HT concentration,74 increased platelet 5-HT uptake75 and increased platelet 3H imipramine binding76 have been found in alcoholics whether drinking or abstaining. However, the same abnormalities occur in other conditions, notably depression and impulsive disorders, and in some of the above studies the alcohol-dependent patients also had anxiety and depressed mood.72-74 Levels of depression were not stated by Daoust et al,75 while the patients of Patkar76,77 were described as alcohol-dependent subjects who were not being treated for depression. Nevertheless, Sellers et al51 point out that the effects of SSRIs on alcohol consumption in short-term clinical trials are dose-related and independent of their antidepressant action. Patkar et al77 also reported a strong positive correlation between craving for alcohol and platelet-rich plasma 5-HT...

Blocking Agents

Inducers of cytochrome P450 such as indole-3-carbinol may increase the metabolic activation of procarcinogens (Rendic and Di Carlo, 1997). Ironically, this often is a necessary step in the detoxification process. In other words, more ultimate carcinogenic derivatives are formed, but they are constructed in such a way that phase II biotransformation enzymes can dispose of them. Inducers of phase II detoxification enzymes might be more beneficial over inducers of cytochrome P450 because inducers of phase II systems are less likely to result in highly bioactive compounds. Of utmost importance are enhancers of GST activity (Hayes and Pulford, 1995). GSTs catalyse the conjugation between electrophilic highly reactive compounds with glutathione, giving rise to a conjugate that can be excreted via urine or faeces. Many dietary anticarcinogens such as vitamins, indole-3-carbinol, limonene and phenyl isothiocyanate are inducers of GSTs in the gastrointestinal tract (Van Lieshout et al., 1996,...

Hepatic Failure

Because of the complexity of liver metabolism, patients with liver disease may develop many complications, including neurological dysfunction. This problem can be expected, considering the important role the liver plays in both nutrient metabolism (glycolysis, nutrient biosynthesis) and detoxification. The term HE refers to diffuse cerebral dysfunction occurring secondary to liver disease. When HE develops acutely in patients with liver disease of less than 8 weeks' duration, the term fulminant hepatic failure (FHF) is used, whereas the term portal-systemic encephalopathy (PSE) is used when HE develops in patients with chronic liver disease. This differentiation has therapeutic implications because a number of treatments exist for patients with PSE, whereas no specific form of treatment has been proved beneficial in FHF, except urgent liver transplantation. Pathogenesis and Pathophysiology. Although neither the responsible toxin nor the pathogenesis of HE is known, it is believed to...


Molecular pharmacogenomics may improve cancer therapy by predicting disease response to specific drug regimens and in reducing side effects and toxicity. The customization of therapy based on molecular targets is exemplified by the treatment of patients with acute promyelocyte leukaemia with all-trans-retinoic acid. This form of acute myeloid leukaemia is characterized by a t(15 17) translocation that involves the retinoic acid receptor-a and treatment with trans-retinoic acid induces differentiation with the majority of patients cured of their leukaemia (Slack and Rusiniak, 2000). Analysis of patient's enzyme systems or genes for drug metabolism and detoxification as well as tumour-specific factors such as the presence or absence of multiple drug-resistant genes may lead to improvements in selection of active drugs, their dosage and timing of therapy. However, the molecular foundations for determination of a tumour's resistance or sensitivity to specific chemotherapies is still not...

Twelvestep Programs

In 1935 Bill Wilson, a stockbroker, and Bob Smith, a physician, met for the first time in Akron, Ohio. Both men were struggling with the disease of alcoholism. Bob did not want another person preaching to him about staying sober, but he agreed to see Bill for a few minutes. The two men talked about their common problem and shared their experiences. Bill explained that he was not there to keep Bob sober he was there to keep himself sober. He had a spiritual awakening during his last detoxification, but it was not enough to keep him sober. He had just lost a business deal, and he was thinking about drinking to ease the pain. Medical science had no answer for the chronic alcoholic at the time. The men talked for hours, and they struck a bond. They found that if they talked about their common problems, they could overcome the compulsion to drink. From this first meeting, .Alcoholics .Anonymous (AA) was born. AAis a fellowship of men and women who share their strength and hope with each...


Eosinophils also have a special propensity to collect in tissues in which allergic reactions occur, such as in the peribronchial tissues of the lungs in people with asthma and in the skin after allergic skin reactions. This is caused at least partly by the fact that many mast cells and basophils participate in allergic reactions, as we discuss in the next paragraph. The mast cells and basophils release an eosinophil chemotactic factor that causes eosinophils to migrate toward the inflamed allergic tissue. The eosinophils are believed to detoxify some of the inflammation-inducing substances released by the mast cells and basophils and probably also to phagocytize and destroy allergen-antibody complexes, thus preventing excess spread of the local inflammatory process.

Central Connections

There is evidence that small water-soluble proteins, termed odorant-binding proteins, assist the movement of some hydrophobic lipid-soluble molecules through the mucus to the receptor proteins of the olfactory cilia. y Such assistance may be selective, and at least some of these proteins may serve to inactivate odorant molecules or filter the number of such molecules reaching the receptors. For example, some odor-induced signals appear to be rapidly abolished by detoxification or biotransformation enzymes within the mucus.y

Gastric Cancer

Genetic polymorphisms may also contribute to gastric cancer risk. Inherited differences in the ability to detoxify potential carcinogens, and inherited variations in the ability to induce transcription or programmed cell death might explain some familial clusters of gastric cancer. The glutathione -transferase enzyme system represents an example of a polymorphism that may favour the development of gastric cancer. These enzymes catalyse the conjugation of numerous carcinogens. Persons lacking the mu form of this enzyme (GSTM1) constitute 40 of the Japanese population and absence of this form of the enzyme increases the risk of developing gastric cancer (Katoh et al., 1996). A similar finding has been noted in an English study. Smoking increases the risk of both gastric cancer and its precursor lesion, intestinal metaplasia of the stomach lining. The null variant of this enzyme may contribute to the increased gastric cancer risk associated with smoking due to alterations in the...

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