Tetrachloroethylene metabolism by the hepatic microsomal cytochrome P-450 system
| Autor: | Anita K. Costa, Kathryn M. Ivanetich |
|---|---|
| Rok vydání: | 1980 |
| Předmět: |
Male
Pregnenolone Carbonitrile Tetrachloroethylene Cytochrome Metabolite In Vitro Techniques Biochemistry chemistry.chemical_compound Cytochrome P-450 Enzyme System medicine Animals Trichloroacetic acid Pharmacology biology Chemistry Metabolism NADPH oxidation Rats Kinetics Phenobarbital Microsomes Liver biology.protein Microsome Oxidation-Reduction NADP medicine.drug |
| Zdroj: | Biochemical Pharmacology. 29:2863-2869 |
| ISSN: | 0006-2952 |
| Popis: | The interaction of tetrachloroethylene with hepatic microsomal cytochromes P-450 has been investigated using male Long-Evans rats. The spectral binding of tetrachloroethylene to cytochromes P-450 in hepatic microsomes from uninduced rats was characterized by a K s of 0.4 mM. The K s was not affected by phenobarbital induction, but was increased following pregnenolone-16α-carbonitrile induction. The K M of 1.1 mM, calculated for the conversion of tetrachloroethylene to total chlorinated metabolites by the hepatic microsomal cytochrome P-450 system, was decreased by phenobarbital induction and increased by pregnenolone-16α-carbonitrile induction. The maximum extents of binding (Δ A max ) and metabolism ( V max ) of tetrachloroethylene were increased by both phenobarbital and pregnenolone-16α-carbonitrile induction. Induction with β-naphthoflavone was without effect on any of the above parameters. The effects of the inducing agents on tetrachloroethylene-stimulated CO-inhibitable hepatic microsomal NADPH oxidation followed the same trend as their effects on V max for the metabolism of tetrachloroethylene, although in all cases the extent of NADPH oxidation was 5- to 25-fold greater than the extent of metabolite production. The inhibitors of cytochromes P-450, viz. metyrapone, SKF 525-A, and CO, inhibited the hepatic microsomal binding and metabolism of tetrachloroethylene. Free trichloroacetic acid was found to be the major metabolite of tetrachloroethylene from the hepatic microsomal cytochrome P-450 system. Neither 2.2,2-trichloroethanol nor chloral hydrate was produced in measurable amounts from tetrachloroethylene. A minor but significant metabolite of tetrachloroethylene by cytochrome P-450 was the trichloroacetyl moiety covalently bound to components of the hepatic microsomes. Incubation of tetrachloroethylene. an NADPH-generating system. EDTA and hepatic microsomes was without effect on the levels of microsomal cytochromes P-450, cytochrome b 5 , beme, and NADPH-cytochrome c reductase. It is concluded that hepatic microsomal cytochromes P-450 bind and metabolize tetrachloroethylene. The major product of this interaction is trichloroacetic acid, which is also the major urinary metabolite of tetrachloroethylene in vivo . The forms of cytochrome P-450 that bind and metabolize tetrachloroethylene include those induced by pregnenolone-16α-carbonitrile and by phenobarbital. Cytochrome P-448. which was induced in rat liver by β-naphthoflavone, does not appear to spectrally bind or metabolize tetrachloroethylene. The metabolism and toxicity of tetrachloroethylene are considered in relation to other chlorinated ethylenes. |
| Databáze: | OpenAIRE |
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