Trifluoroacetylation cytochrome

J Am Acad Child Adolesc Psychiatry 40 622-629 Satoh H, Gillette JR, Davies HW, Schulick RD, Pohl LR (1985) Immunochemical evidtaice of trifluoroacetylated cytochrome P-450 in the liver of halothane-treated rats. Mol Pharmacol 28 468 74... 

Oxidative dehalogenation. Halogen atoms may be removed from xenobiotics in an oxidative reaction catalyzed by cytochromes P-450. For example, the anesthetic halothane is metabolized to trifluoroacetic acid via several steps, which involves the insertion of an oxygen atom and the loss of chlorine and bromine (Fig. 4.28). This is the major metabolic pathway in man and is believed to be involved in the hepatotoxicity of the drug. Trifluoroacetyl chloride is thought to be the reactive intermediate (see chap. 7). 

The involvement of the lysine residues has been explored. Thus, trifluoroacetylation of lysine residues 13, 55 and 99 has been carried out,662 but only modification of residue 13 affects the reaction with cytochrome oxidase. Modification of lysine residues 13, 25, 27, 72 and 79 decreased the reaction rate of cytochrome c with cytochrome bs. It is possible that the lysine groups in unmodified cytochrome c interact with the carboxylate groups in cytochrome b5 (Asp-48, Glu-43, Glu-44 and Asp-60) and one of the heme propionate groups.663 In general, such studies support the proposal that these lysine groups represent binding sites for redox partners of cytochrome c. 

The kinetics of oxidation of a trifluoroacetylated derivative of horse-heart ferro-cytochrome c by hexacyanoferrate(iii) have been measured as a function of temperature a rate constant (25 °C and 7=0.1 mol 1 ) of 3.0 x 10 1 mol" s was obtained, with H =0.4 kcal mol and = — 33 cal mol . The low value of A77 with the modified cytochrome (which does not bind the oxidizing agent) is similar to that found with the native protein (which does) and it is suggested that in the former case the mechanism involves a pre-equilibrium between two forms of the cytochrome, one of which is more easily oxidized. The reaction of [nitrotyrosyl] cytochrome c with imidazole is biphasic and the kinetics are consistent with the existence of a similar equilibrium involving two forms of the cytochrome. 

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