The reductive metabolism of halogenated alkanes by liver microsomal cytochrome P450

Under anaerobic conditions various polyhalogenated alkanes (CCl3-CCl3, HCl2C-CCl3, CF3-CCl3, CCl4, CF-CHCIBr) stimulate the oxidation of NADPH by liver microsomal fractions. The participation of cytochrome P450 in the NADPH oxidation was shown by inducers and inhibitors of the monooxygenase system. The products of the reductive pathway of hexachloroethane were tetrachloroethene (99.5%) and pentachloroethane (0.5%). From pentachloroethane as substrate trichloroethene (96%) and tetrachloroethane (4%) were produced. The stoichiometry of NADPH oxidation and product formation was close to 1:1. There was a synergistic effect in the presence of NADPH and NADH for both hexa- and pentachloroethane. The influence of dioxygen and radical traps (RSH) on the formation of products from hexachloroethane with reduced cytochrome P450 has been investigated. The results indicate the possibility of a reductive in vivo metabolism of polyhalogenated alkanes even at physiological dioxygen concentrations. For the reductive dehalogenation of polyhalogenated alkanes by microsomal cytochrome P450 a reaction scheme is proposed: the reduction proceeds by two subsequent one electron reductions forming first a radical and then a carbanion. The carbanion can form an alkene via beta-elimination of chloride.