Effects of indole-3-carbinol on the metabolism of 4-(methylnitrosamino) 1-(3-pyridyl)-1-butanone in smokers

Indole-3-carbinol (I3C) is a component of the human diet, occurring as a conjugate in certain cruciferous vegetables. I3C protects against carcinogenesis in a variety of animal models by modifying carcinogen metabolism. In mice, I3C decreases lung tumor formation by the tobacco- specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by enhancing its hepatic clearance (M. A. Morse et a., Cancer Res., 50: 2613- 2617, 1990). In this study, our goal was to determine whether I3C would have similar effects on NNK metabolism in smokers as it did in mice. Thirteen women took 400 mg of I3C on 5 consecutive days and maintained constant smoking habits during this period. Their urine was analyzed before and after the I3C treatment period for two metabolites of NNK: 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc). I3C treatment resulted in decreased levels of urinary NNAL, NNAL-Gluc, and NNAL plus NNAL- Gluc, and increased NNAL-Gluc:NNAL ratio in 10 of the 13 women. The mean decreases in NNAL (-0.27 ± 0.09 pmol/mg creatinine, -23.4%) and NNAI, plus NNAL-Gluc (-0.43 ± 0.16 pmol/mg creatinine, -10.9%) were statistically significant as was the increase in NNAL-Gluc:NNAL ratio (1.1 ± 0.5, 39.9%). These changes in urinary metabolites of NNK were consistent with those seen in mice treated with I3C and NNK; they suggest that I3C increased hepatic metabolism of NNK in our smokers. This is the first study to examine the effects of I3C on metabolism of an exogenous carcinogen in humans.