Induction of hepatic CYP1A by indole-3-carbinol in protection against aflatoxin B1 hepatocarcinogenesis in rainbow trout.
This study examined the significance of hepatic cytochrome P4501A (CYP1A) induction in the inhibition of aflatoxin B1 (AFB1)-DNA adduction by indole-3-carbinol (I3C) in rainbow trout. I3C, fed prior to [3H]AFB1 exposure, provided dose-dependent inhibition of hepatic AFB1-DNA binding, which appeared to vary inversely with hepatic CYP1A-mediated ethoxyresorufin O-deethylase (EROD) activity (r = -0.81, P = 0.051). However, 1000 ppm dietary 13C inhibited AFB1-DNA adduction without detectably inducing CYP1A protein or EROD activity. Dietary I3C was found to inhibit AFB1-DNA adduction by approximately 50%, whether [3H]AFB1 was injected ip 1, 2, 3, 5 or 7 days after the onset of I3C feeding, yet hepatic EROD activity was only transiently induced over this period and was not correlated with AFB1-DNA inhibition. Microsome-catalysed AFB1-DNA binding in vitro did correlate inversely with EROD activity in microsomes from control- and I3C-treated trout (r = -0.955, P = 0.01), but data obtained using microsomes from beta-naphthoflavone-treated trout suggest that this observation may not be indicative of a cause-and-effect relationship. I3C-mediated reduction in covalent binding was not due to I3C derivatives in the microsomal preparation or to reduced CYP protein levels, but may reflect a lower microsomal catalytic capacity for AFB1 epoxidation as a result of enzyme inactivation. In addition, the major I3C derivative found in liver, 3,3'-diindolylmethane, has been shown to be a non-competitive inhibitor of EROD, and of enzymes that catalyse AFB1 epoxidation. These findings indicate little, if any, role for CYP1A induction in the inhibition of AFB1 carcinogenicity in rainbow trout by levels of I3C likely to be encountered in cruciferous vegetables.
Takahashi
N
N
Department of Food Science & Technology, Oregon State University, Corvallis 97331, USA.
Stresser
D M
DM
Williams
D E
DE
Bailey
G S
GS
D016604:Aflatoxin B1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects; D018736:DNA Adducts / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D017686:Oncorhynchus mykiss; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects; D013997:Time Factors
D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D007211:Indoles; C072611:aflatoxin B1-DNA adduct; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; C016517:indole-3-carbinol; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1