The role of intestinal microflora in the metabolic activation of 6-nitrochrysene to DNA-binding derivatives in mice.
6-Nitrochrysene has previously been shown to be a potent lung and liver carcinogen following i.p. administration to newborn mice and to be metabolically activated to DNA-binding derivatives by nitro-reduction or a combination of nitro-reduction and ring oxidation. In this study, we have examined fecal metabolites and DNA-carcinogen adducts in 5-week-old conventional and germfree Balb/c mice treated with [3H]6-nitrochrysene in order to determine if the metabolic activation pathway(s) for this compound in these mice differs from that observed in preweanling mice. We further evaluated the role of the intestinal microflora on the metabolism and generation of DNA-reactive metabolites in this system. The amount of 6-aminochrysene excreted in the feces of germfree mice within 48 h after treatment with a single i.p. dose of [3H]6-nitrochrysene (0.03 mumol/5 microliters/g body wt) was approximately 25% of that excreted in identically treated conventional mice. However, the levels of carcinogen-DNA adducts in the lungs and livers of conventional and germfree Balb/c mice were similar at the 24 and 48 h time points examined. HPLC analysis of hydrolysates of liver and lung DNA indicated that adducts derived from both N-hydroxy-6-aminochrysene and trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene metabolites were formed in the liver whereas only the latter adduct was detected in the lung. This contrasts with previous findings in preweanling mice where the adduct derived from the trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene metabolite was the single major adduct detected in both liver and lung DNA. The proportion of adducts derived from N-hydroxy-6-aminochrysene was significantly greater in the liver DNA of germfree mice than in the liver DNA of conventional mice.
Delclos
K B
KB
National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079.
Cerniglia
C E
CE
Dooley
K L
KL
Campbell
W L
WL
Franklin
W
W
Walker
R P
RP
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000378:metabolism / Q000493:pharmacokinetics*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D005243:Feces / Q000032:analysis; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000032:analysis / Q000382:microbiology*; D008099:Liver / Q000032:analysis; D008168:Lung / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000493:pharmacokinetics*
D002273:Carcinogens; D002911:Chrysenes; D004268:DNA-Binding Proteins; D010616:Phenanthrenes; C035986:6-nitrochrysene