Synthesis and mutagenicity of 1-nitropyrene 4,5-oxide and 1-nitropyrene 9,10-oxide, microsomal metabolites of 1-nitropyrene.
[4,5,9,10-(3)H]1-Nitropyrene was incubated with liver microsomes prepared from guinea pigs treated with Aroclor 1254 and the products were examined by h.p.l.c. The previously reported metabolites, 1-nitropyrene trans-4,5-dihydrodiol, 1-nitropyrene trans-9,10-dihydrodiol, and 3-, 6-, and 8-hydroxy-1-nitropyrene were detected. In addition, h.p.l.c., nuclear magnetic resonance and mass spectral analyses indicated the presence of 1-nitropyrene 4,5-oxide and 1-nitropyrene 9,10-oxide. The epoxide hydrase inhibitor, 1,2-epoxy-3,3,3-trichloropropane, decreased the concentration of the 4,5- and 9,10-dihydrodiols in the microsomal incubations and increased the concentration of their corresponding oxides. Reaction of 1-nitropyrene with m-chloroperoxybenzoic acid gave a mixture of 1-nitropyrene 4,5-oxide and 1-nitropyrene 9,10-oxide, which was separated by chromatography. The mutagenicity of the oxides was determined in Salmonella typhimurium strains TA98, TA98NR, and TA98/1,8-DNP6, both with and without exogenous activation by a rat liver homogenate fraction (S9). In the absence of S9, both oxides showed maximum activity in TA98, slightly decreased mutagenicity in the acetylase-deficient strain TA98/1,8-DNP6, and much reduced activity in the nitroreductase-deficient strain, TA98NR. When assayed in the presence of S9, 1-nitropyrene 4,5-oxide had maximum mutagenicity in TA98, and was 50 and 95% less mutagenic in TA98NR and TA98/1,8-DNP6, respectively. 1-Nitropyrene 9,10-oxide had a similar strain sensitivity, except that its total mutagenicity was lower. Since 1-nitropyrene is metabolized by oxidative pathways in vivo, these K-region oxides may contribute to the toxicities elicited by this compound.
Fifer
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National Center for Toxicological Research, Jefferson, AR 72079.
Howard
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Heflich
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Beland
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D000818:Animals; D001711:Biotransformation; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000138:chemical synthesis* / Q000378:metabolism*; D011721:Pyrenes / Q000138:chemical synthesis / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D013057:Spectrum Analysis / Q000379:methods; D014239:Trichloroepoxypropane / Q000494:pharmacology
D009153:Mutagens; D011721:Pyrenes; C057066:1-nitropyrene-4,5-oxide; C057067:1-nitropyrene-9,10-oxide; D014239:Trichloroepoxypropane; D004851:Epoxide Hydrolases; C032668:1-nitropyrene