Effects of neutral salts on hepatic microsomal drug-metabolizing enzyme system in rats.

Effects of neutral salts on the drug-metabolizing enzyme system were measured in hepatic microsomes of rats in vitro. Aminopyrine N-demethylation was markedly enhanced by Li2SO4, Na2SO4, and K2SO4. Salts such as LiCi, NaCl, and KCl caused an enhancement of the demethylation following by an inhibition at high concentrations. KBr, Kl, and KSCN always inhibited the demethylation. Aniline hydroxylation, on the contrary, was not stimulated by the sulfates, and all other salts inhibited the hydroxylation with increasing concentration. The effectiveness of the neutral salts on changing aminopyrine or aniline oxidation activity followed Hofmeister's lyotropic series of ions: SCN- greater than 1- Br- greater than Cl- greater than SO4-- as anions and Li+ greater than Na+, K+ as cations. KSCN, Kl and KBr caused both the conversion of cytochrome P-450 to cytochrome P-420 and the inhibition of NADPH cytochrome c reductase activity; however, all other salts used in these experiments showed no change of those components. Enhancement of aminopyrine N-demethylation by the sulfates was reversible. It was concluded that cytochrome P-450 associated with aminopyrine N-demethylation is different from that of aniline hydroxylation in the hydrophobic environment of microsomes, and sulfate or chloride causes an enhancement of only cytochrome P-450 activity associated with the demethylation.