Tetrachloroethylene metabolism by the hepatic microsomal cytochrome P-450 system
Costa, AK; Ivanetich, KM
HERO ID
58141
Reference Type
Journal Article
Year
1980
Language
English
PMID
| HERO ID | 58141 |
|---|---|
| In Press | No |
| Year | 1980 |
| Title | Tetrachloroethylene metabolism by the hepatic microsomal cytochrome P-450 system |
| Authors | Costa, AK; Ivanetich, KM |
| Journal | Biochemical Pharmacology |
| Volume | 29 |
| Issue | 20 |
| Page Numbers | 2863-2869 |
| Abstract | 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 Ks of 0.4 mM. The Ks was not affected by phenobarbital induction, but was increased following pregnenolone-16α-carbonitrile induction. The KM 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 (ΔAmax) and metabolism (Vmax) 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 Vmax 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 b5, 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. |
| Doi | 10.1016/0006-2952(80)90023-4 |
| Pmid | 7437086 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Biochem. Pharmacol. 29: 2863-2869. |
| Is Public | Yes |
| Language Text | English |
| Is Qa | No |