Synthesis and mutagenicity of 1-nitropyrene 4,5-oxide and 1-nitropyrene 9,10-oxide, microsomal metabolites of 1-nitropyrene

Mutagenesis. 1986 Nov;1(6):433-8. doi: 10.1093/mutage/1.6.433.

Abstract

[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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biotransformation
  • Epoxide Hydrolases / antagonists & inhibitors
  • Guinea Pigs
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / metabolism*
  • Mutagenicity Tests / methods
  • Mutagens / chemical synthesis*
  • Mutagens / metabolism*
  • Pyrenes / chemical synthesis
  • Pyrenes / metabolism*
  • Pyrenes / toxicity*
  • Rats
  • Rats, Inbred Strains
  • Salmonella typhimurium / drug effects
  • Spectrum Analysis / methods
  • Trichloroepoxypropane / pharmacology

Substances

  • Mutagens
  • Pyrenes
  • 1-nitropyrene-4,5-oxide
  • 1-nitropyrene-9,10-oxide
  • Trichloroepoxypropane
  • Epoxide Hydrolases
  • 1-nitropyrene