Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism

A range of potential chemoprotective agents, most of them natural dietaryconstituents, has been examined for ability to modulate both phase I(cytochrome P450 1A1, 1A2, 2B1/2, 2C11, 2E1, 3A, 4A) and phase II drugmetabolizing enzymes (glutathione S-transferases, in particular subunitsYc2 and P, aflatoxin B1-aldehyde reductase and quinone reductase) in ratliver. In addition to assays of total enzyme activity and Western blots forindividual isozymes, the ability of microsomes to metabolize aflatoxin B1,and of cytosols to conjugate aflatoxin B1 (AFB1)-epoxide to GSH and toproduce AFB1-dialcohol, were measured. Induction of gamma-glutamyltranspeptidase activity was examined by histochemistry. Differing patternsof induction were observed, reflecting differences in the control ofexpression of the individual enzymes studied. Of the compounds examined,butylated hydroxytoluene, ethoxyquin, indole-3-carbinol and phenethylisothiocyanate were the most potent bifunctional agents (inducing bothphase I and II activities). Oltipraz, while only weakly inducing CYP1A2 and2B1/2, was a potent inducer of phase II enzymes. Caffeic acid, garlic oil,sinigrin and propyl gallate all showed some ability to induce phase IIenzymes. 4-Methyl catechol, alpha-tocopherol and red wine decreased certainphase I enzyme activities, while inducing total GST activity. Butylatedhydroxytoluene, ethoxyquin, garlic oil and indole-3-carbinol induced gammaglutamyltranspeptidase in periportal hepatocytes. Particularly because oftheir ability to induce the detoxifying activities of glutathioneS-transferase Yc2 and aldehyde reductase, butylated hydroxytoluene,ethoxyquin, indole-3-carbinol, oltipraz, phenethyl isothiocyanate andsinigrin will be effective blocking agents in rodents, if administeredprior to AFB1. While these studies indicate the relative contributions ofphase I and II metabolism in the overall protective effect in rat, careshould be taken that a similar balance is achieved in man, and thatrelevant enzymes or iso forms are induced.