Effects of Chlorinated Ethylenes on Expression of Rat CYP Forms : Comparative Study on Correlation between Biological Activities and Chemical Structures

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Chlorinated ethylenes (CEs) such as tetrachloroethylene (PCE), trichloroethylene (TCE), 1,1-dichloroethylene (1,1-DCE), cis-1,2-dichloroethylene (cis-DCE), and trans-1,2-dichloroethylene (trans-DCE) are members of the class of volatile halogenated hydrocarbons. Each was administered intraperitoneally at 0.5g/kg alone or simultaneously with phenobarbital (PB, 80mg/kg/d) to male Wistar rats weighing about 200g (7-weeks-old). Microsomal fractions of livers and lungs removed from animals sacrificed 24h after treatment were tested for monooxygenase activities and protein content of 4 cytochrome P450 (CYP) forms, i.e., CYP1A1/2,2B1/2,2E1 and 3A1/2. In terms of constitutive expression, they were compensatory in liver and lung with CYP1A1/2,2E1 and 3A1/2 being detected only in liver and CYP2B1 only in lung. All 5 CEs employed in this work suppressed hepatic CYP1A1/2,2E1 and 3A1/2 in the descending order of 1,1-DCE > cis-DCE > trans-DCE > TCE > PCE. The magnitude of suppression of pulmonary CYP2B1 by CEs were compared as follows; PCE > trans-DCE > 1,1-DCE > cis-DCE > TCE. CYP1A1/2,CYP2E1 and CYP3A1/2 in hepatic microsomes from PB-treated animals responded to CEs similarly to those from PB-untreated animals. These 3 enzyme activities could not be detected in pulmonary microsomal fractions, irrespective of the PB-treatment. Hepatic CYP2B1/2 could be detected only when treated with PB in marked contrast to the constitutive expression of pulmonary CYP2B1. The suppression of PB-induced hepatic CYP2B1/2 was observed with all 5 CEs, with special emphasis on complete inhibition with 1,1-DCE. The adverse effects of TCE and PCE on pulmonary CYP2B1 from PB-treated rats were comparable with those from PB-untreated animals. In contrast, 3 dichloro-isomers were more suppressive to the enzyme in the absence than in the presence of PB. The protein levels of hepatic CYP forms were generally proportional to the enzyme activities in the case of 1,1-DCE-treatment. The amounts of pulmonary CYP2B1 apoprotein were in good accordance with the enzyme activities when treated with CEs individually.
公益社団法人日本薬学会の論文
2000-08-01

Effects of Chlorinated Ethylenes on Expression of Rat CYP Forms : Comparative Study on Correlation between Biological Activities and Chemical Structures

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