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.