Abstract
We studied the effects of 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irgasan DP300) on the kinetics of the cytochrome P450 (P450)-dependent monooxygenases in rat liver microsomes. The activities of 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) in rat liver microsomes exposed to 3-methylcholanthrene (MC) and phenobarbital (PB) respectively, were substantially inhibited by Irgasan DP300. The inhibition profile of EROD was competitive, whereas that of PROD was noncompetitive; the Ki values from Hanes plots were 0.24 and 1.48 microM for EROD and PROD, respectively. Phenacetin O-deethylase (PCOD) and 4-nitrophenol hydroxylase (4NPH) activities in rats exposed to PB were also inhibited by Irgasan DP300, at Ki values lower than those for other microsomes. Irgasan DP300 slightly inhibited testosterone 6 beta-hydroxylase (TS6BH) activities in some microsomes. No effect of Irgasan DP300 on lauric acid omega-hydroxylase (LAOH) activity was evident in any microsomal preparations. These results indicated that Irgasan DP300 inhibits MC- and PB-inducible P450-dependent monoxygenase in vitro competitively or noncompetitively, and that the P450 enzymes of the CYP1A or CYP2B subfamily may contribute to Irgasan DP300 toxicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aryl Hydrocarbon Hydroxylases*
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Binding, Competitive
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Blotting, Western
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Carcinogens / toxicity
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP2B1
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Cytochrome P-450 CYP2E1
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Cytochrome P-450 CYP4A
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Cytochrome P-450 Enzyme Inhibitors*
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Cytochrome P-450 Enzyme System / metabolism
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Enzyme Inhibitors / toxicity*
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Fluorometry
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GABA Modulators / toxicity
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Male
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Methylcholanthrene / toxicity
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Microsomes, Liver / drug effects*
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Microsomes, Liver / enzymology
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Mixed Function Oxygenases / antagonists & inhibitors*
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Mixed Function Oxygenases / metabolism
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Oxidoreductases / antagonists & inhibitors*
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Oxidoreductases / metabolism
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Phenobarbital / toxicity
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Rats
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Rats, Wistar
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Software
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Steroid Hydroxylases / antagonists & inhibitors
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Steroid Hydroxylases / metabolism
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Triclosan / toxicity*
Substances
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Carcinogens
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Cytochrome P-450 Enzyme Inhibitors
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Enzyme Inhibitors
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GABA Modulators
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Triclosan
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Methylcholanthrene
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Cytochrome P-450 Enzyme System
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Mixed Function Oxygenases
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Oxidoreductases
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Steroid Hydroxylases
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Cytochrome P-450 CYP2E1
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Aryl Hydrocarbon Hydroxylases
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP2B1
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testosterone 7-alpha-hydroxylase, hamster
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Cytochrome P-450 CYP4A
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Phenobarbital