Ligand Binding of Organic Sulfides to Microsomal Cytochrome P‐450

Abstract

Octyl methyl-, butyl methyl- and pentamethylene sulfide react with about 50 % of oxidized cyto-chrome P-450 in liver microsomes from phenobarbital-pretreated rats by formation of optical dif-ference spectra with maxima at 435 and 552 nm and concomitant shifts in the electron paramagnetic resonance spectrum. Reduction by NADPH or sodium dithionite yielded a Soret absorption band at 449 nm and α and β bands at 573 and 545 nm, respectively. The ligand metyrapone and the substrate n-octane competitively inhibited the formation of these difference spectra and pentamethylene sulfide was a strong competitive inhibitor of the O-dealkylation of 7-ethoxycoumarin. These results indicate a direct ligand binding of the sulfides to cytochrome P-450 with concomitant blocking of the hydrophobic substrate binding site. Some sulfides did not interact as ligands but as substrates, in variation, however, with the source of microsomes.