Metabolism of the carcinogen [3H]6-nitrochrysene in the preweanling mouse: identification of 6-aminochrysene-1,2-dihydrodiol as the probable proximate carcinogenic metabolite.
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.
Delclos
K B
KB
National Center for Toxicological Research, Division of Biochemical Toxicology, Jefferson, AR 72079.
el-Bayoumy
K
K
Hecht
S S
SS
Walker
R P
RP
Kadlubar
F F
FF
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002911:Chrysenes / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D010616:Phenanthrenes / Q000378:metabolism*; D014316:Tritium
D002273:Carcinogens; D002911:Chrysenes; D010616:Phenanthrenes; D014316:Tritium; C057269:6-aminochrysene-1,2-dihydrodiol; C035986:6-nitrochrysene; D004247:DNA