Cytochrome P-450, reductive metabolism, and cell injury

Abstract

A variety of organic compounds such as carbon tetrachloride, halothane, gentian violet, and benznidazole are reductively metabolized to free radicals by liver microsomal cytochrome P-450. Due to the fact that this metabolic activation occurs at a site where O2 usually becomes activated during the monooxygenase cycle, there is a competition between these xenobiotics and O2 for electrons. Reductive activation occurs at a maximal rate under anaerobic conditions. Cell injury may be directly produced by the reactive metabolites. It may also result from lipid peroxidation induced by interaction of the free radicals with polyunsaturated fatty acids of membrane phospholipids. For polyhalogenated alkanes the latter process is most likely the one leading to cell death. When loss of cell viability is mediated by lipid peroxidation, a complex O2 dependence may result, characterized by a maximum loss of cell viability at oxygen partial pressures (PO2) between 1 and 10 mm Hg. These PO2 values are found in the centrilobular area of the liver lobule.