Carcinogenesis, Vol 18, 1729-1738, Copyright © 1997 by Oxford University Press
MM Manson, HW Ball, MC Barrett, HL Clark, DJ Judah, G Williamson and GE Neal
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.
ARTICLES
Mechanism of action of dietary chemoprotective agents in rat liver: induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism
MRC Toxicology Unit, University of Leicester, UK.
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