Subanesthetic concentrations of drugs inhibit cytochrome P450-mediated metabolism of aniline

Abstract

We reported previously that 18 compounds varying in general anesthetic potency by up to 66000-fold inhibited, at anesthetic concentrations, the metabolism of arachidonic acid and aminopyrine by cytochrome P450 monooxygenases in rat liver microsomes. Now, we report that P450-mediated para-hydroxylation of aniline is more sensitive to the anesthetics. The K_i values for enzyme inhibition for seven compounds were close to and for seven compounds 5–40 times less than their respective anesthetic potencies. Endogenous substrates with an aniline-like binding mode to P450 include histamine and related imidazoles. Acetone and each of the halogenated compounds, halothane, enflurane, and chloroform, stimulated aniline hydroxylase activity at concentrations well below and above their EC₅₀ values. These potent actions on the universal P450 isozymes may contribute to pharmacological effects of the anesthetics associated with levels of drug well below concentrations that effect general anesthesia.