Interaction of Drugs, Steroids and Fatty Acids with Liver-Microsomal Cytochrome P-450

Abstract

The interaction of various substrates with the cytochrome P-450 containing monooxygenase system of rat liver microsomes has been studied. Testosterone, triamcinolone acetonide (TrA) and laurate were found to interfere with the type I spectral changes produced by the addition of hexobarbital and ethylmorphine to suspensions of microsomes suggesting that these substrates bind to a common cytochrome P-450 species. Substrates producing a type I spectral change with liver microsomes, such as ethylmorphine, hexobarbital, aminopyrine, laurate and testosterone enhanced the rate of NADPH-linked cyto-chrome P-450 reduction. TrA, on the other hand, did not elicit a type I spectral change and did not stimulate the rate of reduction of the cytochrome. However, TrA interfered with the stimulation of this rate by hexobarbital and aminopyrine. Furthermore, when two compounds which stimulate the rate of cytochrome P-450 reduction were present together, there were no additive effects in stimulation of this rate. In fact, there was a diminution of the stimulation observed when the more potent of the two was present alone. The results suggest that the substrates of the liver-microsomal monooxygenase system studied interact with a single cytochrome P-450 species and that the competitive inhibition they exert on each other's metabolism may be related to an interference with the binding to cytochrome P-450.