INDUCTION OF HEPATIC CYP1A BY INDOLE-3-CARBINOL IN PROTECTION AGAINSTAFLATOXIN B-1 HEPATOCARCINOGENESIS IN RAINBOW-TROUT

This study examined the significance of hepatic cytochrome P4501A (CYP 1A) induction in the inhibition of aflatoxin B-1 (AFB(1))-DNA adductio n by indole-3-carbinol (I3C) in rainbow trout. I3C, fed prior to [H-3] AFB(1) exposure, provided dose-dependent inhibition of hepatic AFB,-DN A binding, which appeared to vary inversely with hepatic CYP1A-mediate d ethoxyresorufin O-deethylase (EROD) activity (r = -0.81, P = 0.051). However, 1000 ppm dietary I3C inhibited AFB,-DNA adduction without de tectably inducing CYP1A protein or EROD activity. Dietary I3C was foun d to inhibit AFB,-DNA adduction by approximately 50%, whether [H-3]AFB , 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 peri od and was not correlated with AFB(1)-DNA inhibition. Microsome-cataly sed AFB(1)-DNA binding in vitro did correlate inversely with EROD acti vity in microsomes from control- and I3C-treated trout (r = -0.955, P = 0.01), but data obtained using microsomes from beta-naphthoflavone-t reated trout suggest that this observation may not be indicative of a cause-and-effect relationship. I3C-mediated reduction in covalent bind ing was not due to I3C derivatives in the microsomal preparation or to reduced CYP protein levels, but may reflect a lower microsomal cataly tic capacity for AFB(1) epoxidation as a result of enzyme inactivation . In addition, the major I3C derivative found in liver, 3,3'-diindolyl methane, has been shown to be a non-competitive inhibitor of EROD, and of enzymes that catalyse AFB(1) epoxidation. These findings indicate little, if any, role for CYP1A induction in the inhibition of AFB(1) c arcinogenicity in rainbow trout by levels of I3C likely to be encounte red in cruciferous vegetables.