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

Abstract

A range of potential chemoprotective agents, most of them natural dietary constituents, has been examined for ability to modulate both phase I (cytochrome P450 1A1, 1A2, 2B1/2, 2C11, 2E1, 3A, 4A) and phase II drug metabolizing enzymes (glutathione S-transferases, in particular subunits Yc2 and P, aflatoxin B1-aldehyde reductase and quinone reductase) in rat liver. In addition to assays of total enzyme activity and Western blots for individual isozymes, the ability of microsomes to metabolize aflatoxin B1, and of cytosols to conjugate aflatoxin B1 (AFB1)-epoxide to GSH and to produce AFB1-dialcohol, were measured. Induction of gamma-glutamyl transpeptidase activity was examined by histochemistry. Differing patterns of induction were observed, reflecting differences in the control of expression of the individual enzymes studied. Of the compounds examined, butylated hydroxytoluene, ethoxyquin, indole-3-carbinol and phenethyl isothiocyanate were the most potent bifunctional agents (inducing both phase I and II activities). Oltipraz, while only weakly inducing CYP1A2 and 2B1/2, was a potent inducer of phase II enzymes. Caffeic acid, garlic oil, sinigrin and propyl gallate all showed some ability to induce phase II enzymes. 4-Methyl catechol, alpha-tocopherol and red wine decreased certain phase I enzyme activities, while inducing total GST activity. Butylated hydroxytoluene, ethoxyquin, garlic oil and indole-3-carbinol induced gamma glutamyltranspeptidase in periportal hepatocytes. Particularly because of their ability to induce the detoxifying activities of glutathione S-transferase Yc2 and aldehyde reductase, butylated hydroxytoluene, ethoxyquin, indole-3-carbinol, oltipraz, phenethyl isothiocyanate and sinigrin will be effective blocking agents in rodents, if administered prior to AFB1. While these studies indicate the relative contributions of phase I and II metabolism in the overall protective effect in rat, care should be taken that a similar balance is achieved in man, and that relevant enzymes or iso forms are induced.

Enhanced cytotoxicity of mitomycin C in human tumour cells with inducers of DT-diaphorase

“…Manson et a (1997) have shown that caffeic acid is a moderate inducer of phase II enzymes, but in our study caffeic acid did not increase DT-diaphorase activity.…”

“…Oltipraz, a D3T analogue, has been shown to induce phase II detoxifying enzymes and is currently undergoing clinical trials as a chemopreventive agent (Kensler and Helzlsouer, 1995). Isothiocyanates like sulforaphane, which is found in broccoli, can also induce phase II enzymes (Prestera et al, 1993;Manson et al, 1997), and have been shown to prevent the formation of carcinogen-induced tumours in animals (Zhang et al, 1994).…”

Chemoprotective activity of the isoflavones, genistein and daidzein on mutagenicity induced by direct and indirect mutagens in cultured HTC cells

“…Thus, phase I enzymes often result in bioactivation compared to inactivation resulting from phase II. According to Manson et al (1997) the result of exposure to an environmental toxin in terms of acute or chronic toxicity largely depends on the balance between these two processes. To better understand the antimutagenic mechanism of genistein on indirect mutagens, we focused on the metabolic activation of phase II enzymes.…”

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

“…Which pharmacologic properties of I3C could instead be implicated? Its ability to block tumor initiation has been rationalized in terms of upregulation of drug metabolizing enzymes, 27 whereas tumor suppression by I3C may be the consequence of modulation of pathways resulting in inhibition of cell proliferation or in compromised cell survival. 28,29 I3C has been shown to protect mice against hepatic damage induced by the hepatotoxicant carbon tetrachloride (CCl 4 ).…”