MECHANISMS OF TUMOR MODULATION BY INDOLE-3-CARBINOL - DISPOSITION ANDEXCRETION IN MALE FISCHER-344 RATS

This study describes the disposition and excretion of indole-3-carbino l (13C), a natural dietary tumor modulator and candidate chemopreventi ve agent, in male Fisher 344 rats after continuous dietary or a single oral administration. Steady-state urinary and fecal excretion were at tained 40 and 112 hr, respectively, after commencing continuous exposu re. These two routes accounted for similar to 75% of the administered dose, of which 77% appeared in feces. After 7 days of 2,000 ppm dietar y 13C, a mean of 1,154 mu M 13C eq was found in liver, of which 17% wa s present as extractable, unbound I3C derivatives. Total equivalents i n liver decreased to 643 and 411 mu M 24 and 48 hr later, respectively , for animals returned to control diet. Mean levels of 13C eq in lung decreased from 436 to 219 mu M, and blood levels decreased from 320 to 208 mu M over the same 48-hr period. After administration of 1 mmol/k g radioinert 13C (a comparable daily dose as in the feeding study) for 6 days, animals were given 1 mmol/kg [H-3]13C. Mean liver levels were 257, 283, and 541 mu M 13C eq at 1.5, 3, and 6 hr after dosing, and t hese levels represented 0.97%, 1.34%, and 2.45% of the total 13C dose administered, respectively. Concentrations of 13C eq changed little in blood, kidney, tongue, or lung over this time period. HPLC analysis o f ethyl acetate extracts of liver from rats given an oral dose reveale d 24 distinct [H-3]13C-derived peaks. Two of the predominant peaks wer e identified as 3,3'-diindolylmethane (133', a linear dimer of 13C) an d [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LT, a linear tri mer). A novel 13C metabolite was identified 1-(3-hydroxymethyl)-indoly l-3-indolylmet Hepatic levels of these metabolites and three major, bu t unidentified, products were between 1.0 and 13.1 mu M; highest level s were observed at 6 hr or, for HI-IM, at 1.5 hr postdosing. Parent 13 C was not detected in liver extracts, whereas the potent Ah receptor a gonist 3,2-b-indolocarbazole (ICZ) was estimated at 1.6 nM. These data suggest that neither 133', LT, or ICZ alone reach sufficient hepatic concentration to account for cytochrome P4501A induction by dietary 13 C, or provide effective inhibition of microsomal bioactivation of the hepatocarcinogen aflatoxin B-1; however, the total hepatic mixture of 13C derivatives may be sufficient to provide both modulatory responses in the rat.