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Effect of 4-tert-octylphenol on cytochrome P450 enzymes in rat liver
N Hanioka1, H Jinno, Y S Chung
1Division of Environmental Chemistry, National Institute of Health Sciences, Tokyo, Japan. hanioka@nihs.go.jp
Abstract:
The effects were studied of 4-tert-octylphenol (OP) on hepatic cytochrome P450 enzymes in rats. Rats were treated intraperitoneally with OP twice, at doses of 5, 10, and 20 mg/kg. Among the cytochrome P450-dependent monooxygenase activities, testosterone 2alpha-hydroxylase activity, which is associated with CYP2C11, was significantly decreased by OP at all doses. The level relative to control activity was 67-22%. CYP3A2-dependent monooxygenase, testosterone 6beta-hydroxylase activity was also decreased by 51% by OP at 20 mg/kg. Furthermore, immunoblotting showed that OP (10 or 20 mg/kg) significantly decreased CYP2C11/6 and CYP3A2/1 protein levels. However, the reduction ratio of CYP2C11/6 and CYP3A2/1 protein levels by OP treatment was lower than that of testosterone 2alpha-hydroxylase and testosterone 6beta-hydroxylase activities. The Cl(int) (Vmax/Km) value for testosterone 2alpha-hydroxylase was significantly decreased by OP at all doses, whereas the Cl(int) value for testosterone 6beta-hydroxylase was only decreased by OP at 20 mg/kg. In addition, 7-ethoxycoumarin O-deethylase activity was significantly decreased by 32% by the highest dose of OP. By contrast, CYP1A1-, CYP1A2-, CYP2A1-, CYP2B1/2-, CYP2D1-, CYP2E1- and CYP4A1/2/3-dependent monooxygenase activities were not affected by OP at any dose. These results suggest that OP changes the male-specific cytochrome P450 isoforms in rat liver, and that these changes closely relate to the toxicity of OP.
Insights
4-tert-octylphenol (OP) significantly alters male-specific cytochrome P450 enzymes in rat liver, impacting testosterone metabolism and potentially contributing to OP toxicity. These findings highlight OP
Area of Science:
- Toxicology
- Biochemistry
- Pharmacology
Background:
- Cytochrome P450 (CYP) enzymes are crucial for xenobiotic metabolism and endogenous compound regulation.
- 4-tert-octylphenol (OP) is an environmental endocrine disruptor with known toxic effects.
- Understanding OP's impact on hepatic CYP enzymes is vital for assessing its toxicological profile.
Purpose of the Study:
- To investigate the effects of 4-tert-octylphenol (OP) on specific hepatic cytochrome P450 (CYP) enzyme activities and protein levels in rats.
- To determine which CYP isoforms are most sensitive to OP exposure.
- To correlate changes in CYP activity with OP toxicity.
Main Methods:
- Rats were administered intraperitoneal injections of OP at varying doses (5, 10, 20 mg/kg).
- Measurement of various CYP-dependent monooxygenase activities, including testosterone 2alpha-hydroxylase and testosterone 6beta-hydroxylase.
- Immunoblotting was used to assess CYP2C11 and CYP3A2 protein levels.
- Determination of intrinsic clearance (Cl(int)) values for specific enzyme activities.
Main Results:
- OP significantly decreased testosterone 2alpha-hydroxylase (CYP2C11-associated) activity at all doses.
- Testosterone 6beta-hydroxylase (CYP3A2-associated) activity was reduced by OP at the highest dose.
- OP treatment led to decreased protein levels of CYP2C11 and CYP3A2, with activity reductions exceeding protein level changes.
- Intrinsic clearance values for testosterone 2alpha-hydroxylase and, at higher doses, testosterone 6beta-hydroxylase were significantly reduced.
- 7-ethoxycoumarin O-deethylase activity was also decreased, while other CYP activities remained unaffected.
Conclusions:
- 4-tert-octylphenol (OP) selectively affects male-specific CYP isoforms (CYP2C11, CYP3A2) in rat liver.
- The observed alterations in CYP enzyme activity and protein levels are closely linked to the toxic effects of OP.
- These findings contribute to understanding the mechanism of OP-induced toxicity through modulation of hepatic drug-metabolizing enzymes.