Enzymatic Detoxication of Tumorigenic Bay-Region Diol-Epoxides of Polycyclic Aromatic Hydrocarbons by Conjugation with Glutathione
Polycyclic aromatic hydrocarbons (PAH), such as benzo(a)pyrene (BP), benz(a)anthracene (BA) and chrysene (C), are widely distributed contaminants in the environment and proven tumorigens in experimental animals. Epidemiological data indicate a role for PAH also in the etiology of certain human tumors1. PAH require metabolic transformation to electrophilic intermediates to exert their toxic effects, most probably through covalent binding of these intermediates to critical targets in DNA. BP is activated through the action of cytochrome P-450-linked monooxygenases and epoxide hydrolase to diastereomeric trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-BP (anti- and syn-BPDE). The (+)-enantiomer of anti-BPDE, with R,S,S,R-absolute configuration, is the most tumorigenic one of the isomers in animals2. Similar results have been obtained with the equivalent diol-epoxides of BA and C3. Furthermore, covalent binding of (+)-anti-BPDE to the exocyclic nitrogen of deoxyguanosine in DNA of target tissues is closely correlated with tumor formation4. Thus, it is likely that enzymatic and non-enzymatic processes that prevent intracellular accumulation of PAH diol-epoxides will counteract DNA-damage and resulting consequences.
KeywordsPolycyclic Aromatic Hydrocarbon Epoxide Hydrolase Glutathione Transferase Polycyclic Hydrocarbon Reversed Phase Analytical Column
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