PMID: 8971135Dec 1, 1996Paper

Characterization of the NADPH-dependent covalent binding of [14C]halothane to human liver microsomes: a role for cytochrome P4502E1 at low substrate concentrations

Drug Metabolism and Disposition : the Biological Fate of Chemicals
A Madan, A Parkinson

Abstract

Activation of halothane to trifluoroacetyl halide, followed by covalent binding to proteins (neoantigen formation) has been proposed to be the mechanism by which halothane causes immune hepatitis. The aim of this study was to identify the cytochrome P450 (CYP) enzyme primarily responsible for the NADPH-dependent covalent binding of [14C]halothane to human liver microsomes. Human liver microsomes were incubated in the absence and presence of NADPH with various concentrations of halothane (from 4.6 to 3,300 microM) to examine the effects of substrate concentration on the nonspecific and specific (NADPH-dependent) binding of [14C]halothane to microsomal protein. As a function of substrate concentration, the specific binding of [14C]halothane to human liver microsomes was biphasic, suggesting that the activation of halothane is catalyzed by a high-affinity enzyme(s) at low substrate concentrations (<150 microM) and by a low-affinity enzyme(s) at high substrate concentrations (>150 microM). For the high-affinity enzyme, the apparent KM for the covalent binding of [14C]halothane was approximately 10 microM, and Vmax was approximately 32 pmol equivalents of halothane bound/mg protein/min under conditions where covalent binding was dir...Continue Reading

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