The strong hepatocarcinogenicity of the electrophilic and mutagenic metabolite 6-sulfooxymethylbenzo[a]pyrene and its formation of benzylic DNA adducts in the livers of infant male B6C3F1 mice.
6-Hydroxymethylbenzo[a]pyrene was activated to an electrophilic and mutagenic sulfuric acid ester metabolite by rat and mouse liver sulfotransferase activity. The intrinsic mutagenicity of this reactive ester, 6-sulfooxymethylbenzo[a]pyrene, was inhibited by glutathione and glutathione S-transferase. A single i.p. dose of 2.5 nmol/g body wt of 6-sulfooxymethylbenzo[a]pyrene in infant male B6C3F1 mice induced liver tumors in 35 of 36 mice at 10 months with an average multiplicity of 4.4. A comparable dose of the parent hydrocarbon, 6-hydroxymethylbenzo[a]pyrene, was only a tenth as active. The electrophilic sulfuric acid ester produced high levels of benzylic DNA adducts in the livers of these mice that accounted for about 80% of the total DNA adducts. These results strongly suggest that this sulfuric acid ester is an important ultimate electrophilic and carcinogenic metabolite in carcinogenesis by 6-hydroxymethylbenzo[a]pyrene and possibly even by 6-methylbenzo[a]pyrene and benzo[a]pyrene in mouse liver.
Surh
Y J
YJ
McArdle Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison 53706.
Liem
A
A
Miller
E C
EC
Miller
J A
JA
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D001711:Biotransformation; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002712:Chlorides / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D005982:Glutathione Transferase / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D012486:Salmonella typhimurium / Q000187:drug effects; D015238:Sulfotransferases / Q000378:metabolism*
D001580:Benzopyrenes; D002273:Carcinogens; D002712:Chlorides; C017409:6-(hydroxymethyl)benzo(a)pyrene; C066039:6-sulfooxymethylbenzo(a)pyrene; D004247:DNA; D005982:Glutathione Transferase; D015238:Sulfotransferases; D005978:Glutathione