Interaction of trichloroethane isomers with cytochrome P-450 in the perfused rat liver.
The real-time interactions of 1,1,1-trichloroethane (TCE) and 1,1,2-TCE with cytochrome P-450 were observed using in vivo optical methods to measure the spectral changes of cytochrome P-450 and the reduction-oxidation transition of pyridine nucleotides in the perfused liver of rats treated with phenobarbital. Changes in oxygen consumption and TCE uptake were also measured. The spectral changes of cytochrome P-450 indicated that both TCE isomers bound to low spin (substrate free) ferric cytochrome P-450 and formed a high spin (substrate complexed) form. However, 1,1,1-TCE bound more tightly to cytochrome P-450 and seemed to be only slowly metabolized compared to 1,1,2-TCE. The stoichiometry of the change in oxygen consumption rate to the change in 1,1,1-TCE uptake rate ranged between 5/1 and 9/1, whereas that of 1,1,2-TCE was 1.4 to 2.0. Decreases in reduced pyridine nucleotides associated with TCE administration were significantly larger with 1,1,1-TCE than with 1,1,2-TCE. The inhibitory effect of 1,1,1-TCE on hexobarbital metabolism in the perfused liver was greater than that of 1,1,2-TCE. Considering our previous data indicating that TCE did not stimulate mitochondrial respiration, it is postulated that the far higher amount of oxygen consumption associated with the binding of 1,1,1-TCE to cytochrome P-450 than the amount which was necessary to mixed-function oxidation of this compound was due to an uncoupling effect of 1,1,1-TCE on the mixed-function oxidase system.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006591:Hexobarbital / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D066298:In Vitro Techniques; D007536:Isomerism; D008099:Liver / Q000201:enzymology*; D008297:Male; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence; D013053:Spectrophotometry; D014240:Trichloroethanes / Q000378:metabolism / Q000633:toxicity*
D006454:Hemoglobins; D006843:Hydrocarbons, Chlorinated; D014240:Trichloroethanes; D009243:NAD; C024566:1,1,1-trichloroethane; C024567:1,1,2-trichloroethane; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital