Metabolism of the carcinogen [3H]6-nitrochrysene in the preweanling mouse: identification of 6-aminochrysene-1,2-dihydrodiol as the probable proximate carcinogenic metabolite

Carcinogenesis. 1988 Oct;9(10):1875-84. doi: 10.1093/carcin/9.10.1875.

Abstract

6-Nitrochrysene (NC) is a potent lung and liver carcinogen when administered in multiple doses to preweanling mice. We have investigated both the in vitro metabolism of [3H]NC by 9000 g supernatants (S9) prepared from the livers of preweanling mice and the in vivo metabolism of [3H]NC in these animals. The in vitro covalent binding of primary metabolites of NC to DNA after further reductive and/or oxidative metabolism was then examined in an attempt to define the metabolic activation pathway responsible for the formation of carcinogen--DNA adducts in NC-treated preweanling mice. NC-1,2-dihydrodiol, NC-9,10-dihydrodiol, 6-aminochrysene (AC), and several unidentified compounds were found in ethyl acetate extracts of incubations containing [3H]NC and liver S9 from 1- or 8-day-old BLU:Ha mice. Comparison of the in vivo metabolism of NC in 1-day-old animals and 8-day-old animals which had been treated with NC on day 1 indicated that the formation of AC and the two NC dihydrodiols was greater in the younger animals. Further metabolism of NC-1,2-dihydrodiol by S9 from 8-day-old mice yielded AC-1,2-dihydrodiol as a major product. Incubation of AC-1,2-dihydrodiol, calf thymus DNA and liver microsomes from 3-methylcholanthrene-induced rats yielded a single major adduct that was chromatographically and chemically identical to the major adduct formed in [3H]NC- and [3H]-AC-treated preweanling mice. The results indicated that the major DNA adduct found in vivo is derived from the further metabolism of the proximate carcinogen AC-1,2-dihydrodiol.

Publication types

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

MeSH terms

  • Animals
  • Biotransformation
  • Carcinogens / metabolism*
  • Chrysenes / metabolism*
  • DNA / metabolism
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mice
  • Mice, Inbred ICR
  • Microsomes, Liver / metabolism*
  • Molecular Structure
  • Phenanthrenes / metabolism*
  • Tritium

Substances

  • Carcinogens
  • Chrysenes
  • Phenanthrenes
  • Tritium
  • 6-aminochrysene-1,2-dihydrodiol
  • 6-nitrochrysene
  • DNA