Pyridine prevents the clastogenicity of benzene but not of benzo[a]pyrene or cyclophosphamide.
Pyridine has been shown to be a much more potent inhibitor than other solvents of the metabolism and therefore the clastogenicity of benzene. In this report, pyridine prevented benzene-derived micronucleus formation in the bone marrow of ICR Swiss mice at much lower levels than xylene did. Time-course experiments did not indicate any delay in the peak micronucleus response to benzene caused by either pyridine or xylene. Similar experiments using pyridine with benzo[a]pyrene and pyridine with cyclophosphamide indicated that the effect of pyridine was specific for benzene. Benzo[a]pyrene (150 mg/kg) was inhibited by pyridine only at levels of 100 mg/kg or more, compared to inhibition of benzene (440 or 880 mg/kg) by pyridine at levels of 5 mg/kg. Cyclophosphamide was not inhibited at any level, and micronucleus formation was increased at lower ratios of pyridine to cyclophosphamide. These results provide indirect conformation of the work by others indicating that benzene is activated in part by a cytochrome P450 isozyme different from those activating benzo[a] pyrene or cyclophosphamide. Since DBA/2 mice (AHH-non-inducible) are more sensitive to benzene than C57Bl/6 mice (AHH-inducible), single and multiple treatments with benzene were compared by micronucleus response in these two strains. DBA mice were more responsive in all cases. Pretreatment with methylcholanthrene caused a greater response to benzene in DBA/2 mice, suggesting that the cytochrome P450 isozyme involved is one of the forms induced by methylcholanthrene independent of the high-affinity Ah receptor. It is hypothesized that more efficient activation of benzene by the unique cytochrome P450 isozyme, perhaps combined with relatively less conjugation, may result in a greater sensitivity of the bone marrow versus the liver, and of DBA/2 versus C57Bl/6 mice.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001554:Benzene / Q000037:antagonists & inhibitors*; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D001711:Biotransformation; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D003520:Cyclophosphamide / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism; D004347:Drug Interactions; D004351:Drug Resistance; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL / Q000378:metabolism; D008811:Mice, Inbred DBA / Q000378:metabolism; D008813:Mice, Inbred ICR; D009152:Mutagenicity Tests; D011725:Pyridines / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects / Q000235:genetics; D014992:Xylenes / Q000494:pharmacology
D003580:Cytochromes; D007527:Isoenzymes; D011725:Pyridines; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D014992:Xylenes; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D001554:Benzene; C023666:pyridine