Structure-activity relationships of dietary indoles: a proposed mechanism of action as modifiers of xenobiotic metabolism.

In an effort to understand the mechanism by which dietary indoles inhibit chemically initiated tumorigenesis in experimental animals, we have investigated the potency of 3-substituted and 1,3-disubstituted indoles on the induction of intestinal and hepatic cytochrome P-448-dependent monooxygenases in the rat. Oral intubation with indole-3-carbinol (13C), 1-methoxyindole-3-carbinol (N13C), 1-methoxyindole-3-carboxaldehyde (NCHO), and 3,3'-diindolylmethane (133') at 31 mumol/animal led to significant increases in hepatic ethoxyresorufin O-deethylase activity (EROD; 15, 7, 6, and 5-fold over control, respectively), while intubation with indole (IND), 3-methylindole (3MI), indole-3-carboxaldehyde (13CHO), and indole-3-acetonitrile (IAN) did not increase this monooxygenase activity over control levels. For the eight indoles tested, there was a strong relationship between instability in acidic solution, as indicated by the generation of insoluble products, and capacity to induce hepatic EROD. Further experiments indicated that 13C did not induce hepatic EROD when dosed ip (thus bypassing the acidity of the stomach). Acid treatment of 13C generated a reaction mixture (RXM) that induced EROD after ip or po dosing. Chromatographic fractionation of the RXM indicated that there exist at least four different 13C acid-condensation products in the RXM with the ability to induce EROD. The results presented strongly support the hypothesis that dietary indoles influence the levels of monooxygenase activities via a series of acid-condensation products generated upon introduction of the indole into the acidic environment of the stomach.