The potential toxicity of oxygen-related side products formed during drug metabolism activities remains a fascinating topic. It has been clearly established that oxygen radicals can peroxidize lipids, thus modifying many membrane properties such as fluidity; these radicals also can depolymerize proteo-glycans (thus altering cell-cell adhesion and communication), oxidize proteins
(resulting in changes in enzyme activities, receptor affinities, transport kinetics, and immunological responsiveness), and finally, alter nucleic acids and their genomic content. In fact, all cell macromolecules are potential targets that can be altered by oxidative stress, resulting frequently in aging-like alterations of their properties (87). Therefore, the reactivity of oxygen radicals appears to be of paramount importance because of their ability to modify many molecular characteristics and specific properties allowing the functioning of both the BBB (88) and the CNS (89). The brain continuously produces superoxide radicals as by-products of aerobic metabolism, and this lifelong radical production results in the formation of abnormal mitochondria and lipofuscin deposits that are characteristic markers of brain aging. The brain is also the most sensitive tissue to oxidative damage, owing to its high and constant requirement for oxygen, as well as high amounts of easily oxidizable or peroxidizable substrates, and non-protein-bound iron in the cerebrospinal fluid.
The formation of oxygen reduction products (superoxide, hydrogen peroxide, or hydroxyl radicals) has been described during the activities of several phase 1 enzymatic systems. The superoxide anion is not considered to be very toxic by itself, but it may form either harmful hydroxyl radicals by Fenton kinetics in the presence of transition metals (90) or peroxynitrite in the presence of nitric oxide (91). The latter is considered to be responsible for most pathological oxidative stress in the living tissue (for a review, see Ref. 92). Since astrocytes possess more efficient scavenging systems than neurons (93), oxidative stress may result in selective neuronal death by promoting necrosis or apoptosis, and an associated increase in passive permeability of the BBB may contribute to human neurodegenerative pathologies such as the following.
1. MAO activity involves the formation of hydrogen peroxide, and this enzyme has been suspected to participate in the global increase of oxidized products in the aged brain (94) and in oxidative damage to the substantia nigra observed in Parkinson's disease (95). Therefore, deprenyl, a specific MAO-B inhibitor, and also a molecule protecting dopamine neurons from peroxyni-trite-promoted apoptosis (96), is frequently coadministered with dopamine agonists for the treatment of Parkinson's disease (73).
2. CYP-dependent activities continuously generate superoxide, as a ''leak'' of reduced oxygen during the catalytic cycle (97). This radical production is increased by inducers of the expression of some CYP isoforms (3MC or BNF) and inhibited by the depletion of NADPH or oxygen, or by selective inhibition of CYP activities. Because superoxide radical may promote the formation of other more toxic radicals, the limited capacity of the cerebral en zymes to be induced by 3MC or BNF can be considered to be a protection mechanism against high activity-promoted oxidative stress.
3. Molecular radicals formed by the one-electron reduction of some xenobiotics by NADPH-cytochrome P450 reductase may react with molecular oxygen to form superoxide. Many quinones display cytotoxic properties that have made them useful as anticancer or antibacterial drugs. The molecular mechanism of their cytotoxicity is generally considered as an enzymatic redox cycling with the participation of NADH- or NADPH-dependent reductases. The enzymatic reduction of quinones results in the formation of semiquinones, followed in aerobic conditions by a reduction of oxygen to superoxide and the regeneration of the parent quinone (98) (Fig. 2). A significant superoxide production during xenobiotic metabolism has been demonstrated in isolated brain microvessels or choroid plexus homogenates and in brain microsomes
The microsomal enzyme involved in superoxide formation by one electron-step reduction of quinones and nitroheterocyclic and imminium compounds has been identified as NADPH-cytochrome P450 reductase. Xenobi-otic-promoted superoxide production has also been observed with neurons, astrocytes, and cerebrovascular endothelial cells in primary cultures, the rate of molecule entry into the cell being a reaction-limiting step (35, 100). Since cerebrovascular endothelial cells are continuously exposed to blood-borne molecules, their metabolic ability toward some xenobiotics may result in the formation of reactive metabolites or oxygen species, probably altering their specific properties, especially their selective permeability (101-103) and also
Fig. 2 Formation of superoxide radicals during the reductive metabolism of xenobi-otics by NADPH-cytochrome P450 reductase in normoxic conditions (redox cycling).
NADPH-cytochrome P450 reductase resulting in a dose-dependent increase in lipid peroxidation products (unpublished observations).
Was this article helpful?