Evidence for the involvement of CYP1A2 in the metabolism of bromodichloromethane in rat liver.
Bromodichloromethane (BDCM) is a drinking water disinfectant by-product that has been implicated in liver, kidney and intestinal cancers in rodents and in intestinal tumors and low birth weight effects in humans. BDCM is also hepatotoxic and requires metabolic activation for both toxicity and carcinogenicity. We have recently reported that CYP1A2 may participate in that metabolism and we now report experiments to support that implication. Induction of CYP1A2 in male F344 rats without inducing CYP2E1 or CYP2B1/2, using TCDD, increased the hepatotoxicity of BDCM when compared to earlier work conducted under similar protocols. Inhibition of CYP1A2, with isosafrole, reduced the metabolism and toxicity of BDCM in the previously induced rats. In addition, specific activities and Western blots for these CYP isoenzymes were measured 24 h after exposure. Activity data show that only CYP1A2 was inhibited by isosafrole; isosafrole forms a complex with CYP1A2 that persists for more than 24 h. Western blot results generally agree with the activity data except that isosafrole induced the protein for all isoenzymes measured. A physiologically based pharmacokinetic model, developed previously, estimated that BDCM metabolism was complete about 7 h after gavage dosing. It is noteworthy that the reduction in CYP1A2 activity was still measurable despite the production of additional CYP1A2 protein during the period of approximately 18 h after BDCM metabolism was complete. These results demonstrate that CYP1A2 does metabolize BDCM and does contribute to hepatotoxicity under certain conditions.
Allis
John W
JW
National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27607, USA.
Anderson
Brian P
BP
Zhao
Guangyu
G
Ross
Tracey M
TM
Pegram
Rex A
RA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015153:Blotting, Western; D001965:Bromides / Q000097:blood; D002273:Carcinogens / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012451:Safrole / Q000494:pharmacology; D022882:Trihalomethanes / Q000378:metabolism*
D001965:Bromides; D002273:Carcinogens; D004338:Drug Combinations; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D022882:Trihalomethanes; C025191:bromodichloromethane; D007064:L-Iditol 2-Dehydrogenase; D019388:Cytochrome P-450 CYP1A2; D000410:Alanine Transaminase; D012451:Safrole; C015959:isosafrole