The anticarcinogen 3,3'-diindolylmethane is an inhibitor of cytochrome P-450.
Dietary indole-3-carbinol inhibits carcinogenesis in rodents and trout. Several mechanisms of inhibition may exist. We reported previously that 3,3'-diindolylmethane, an in vivo derivative of indole-3-carbinol, is a potent noncompetitive inhibitor of trout cytochrome P450 (CYP) 1A-dependent ethoxyresorufin O-deethylase with Ki values in the low micromolar range. We now report a similar potent inhibition by 3,3'-diindolylmethane of rat and human CYP1A1, human CYP1A2, and rat CYP2B1 using various CYP-specific or preferential activity assays. 3,3'-Diindolylmethane also inhibited in vitro CYP-mediated metabolism of the ubiquitous food contaminant and potent hepatocarcinogen, aflatoxin B1. There was no inhibition of cytochrome c reductase. In addition, we found 3,3'-diindolylmethane to be a substrate for rat hepatic microsomal monooxygenase(s) and tentatively identified a monohydroxylated metabolite. These observations indicate that 3,3'-diindolylmethane can inhibit the catalytic activities of a range of CYP isoforms from lower and higher vertebrates in vitro. This broadly based inhibition of CYP-mediated activation of procarcinogens may be an indole-3-carbinol anticarcinogenic mechanism applicable to all species, including humans.
Stresser
D M
DM
Department of Food Science and Technology, Oregon State University, Corvallis 97331-6602, USA.
Bjeldanes
L F
LF
Bailey
G S
GS
Williams
D E
DE
D016604:Aflatoxin B1 / Q000037:antagonists & inhibitors; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D051381:Rats; D011916:Rats, Inbred F344
D016588:Anticarcinogenic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D016604:Aflatoxin B1; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D019362:Cytochrome P-450 CYP2B1; C023738:acetanilide hydroxylase; C016392:3,3'-diindolylmethane