TY - JOUR T1 - Dominant role of cytochrome P-450 2E1 in human hepatic microsomal oxidation of the CFC-substitute 1,1,1,2-tetrafluoroethane. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 518 LP - 524 VL - 20 IS - 4 AU - S E Surbrook, Jr AU - M J Olson Y1 - 1992/07/01 UR - http://dmd.aspetjournals.org/content/20/4/518.abstract N2 - The chlorofluorocarbon substitute 1,1,1,2-tetrafluoroethane (HFC-134a) is subject to metabolism by cytochrome P-450 in hepatic microsomes from rat, rabbit, and human. In rat and rabbit, the P-450 form 2E1 is a predominant low-KM, high-rate catalyst of HFC-134a biotransformation and is prominently involved in the metabolism of other tetrahaloalkanes of greater toxicity than HFC-134a [e.g. 1,2-dichloro-1,1-difluoroethane (HCFC-132b)]. In this study, we determined that the human ortholog of P-450 2E1 plays a role of similar importance in the metabolism of HFC-134a. In human hepatic microsomes from 12 individuals, preparations from subjects with relatively high P-450 2E1 levels were shown to metabolize HFC-134a at rates 5- to 10-fold greater than microsomes of individuals with lower levels of this enzyme; the increased rate of metabolism of HFC-134a was specifically linked to increased expression of P-450 2E1. The primary evidence for this conclusion is drawn from studies using mechanism-based inactivation of P-450 2E1 by diethyldithiocarbamate, competitive inhibition of HFC-134a oxidation by p-nitrophenol (a high-affinity substrate for P-450 2E1), strong positive correlation of rates of HFC-134a defluorination with p-nitrophenol hydroxylation in the study population, and correlation of P-450 2E1 levels with rates of halocarbon oxidation. Thus, our findings support the conclusion that human metabolism of HFC-134a is qualitatively similar to that of the species (rat and rabbit) used for toxicological assessment of this halocarbon.(ABSTRACT TRUNCATED AT 250 WORDS) ER -