Inhibition of microsomal drug oxidations by aliphatic halohydrocarbons: correlation with vapour pressure.
1. The effects of 12 halogenated aliphatic compounds on microsomal N-dealkylation, C-hydroxylation and N-oxidation of N-methylaniline and N-hydroxylation of p-chloroaniline were determined in closed reaction vessels. 2. There is no correlation between the volatility of the agents investigated and their binding characteristics to oxidized or reduced microsomal cytochrome P-450. 3. High correlation was observed between inhibiton of cytochrome P-450-mediated drug oxidations and the boiling points (vapour pressure) of the individual compounds. The N-oxidation of N-methylaniline, which is not catalysed by cytochrome P-450, did not show this correlation. 4. Other factors e.g. ligand formation with reduced cytochrome P-450, lipid peroxidation and haem destruction, production of carbon monoxide, and alterations of microsomal cofactors, did not produce significant inhibition. 5. Many artefacts occur when reaction velocities, inhibition constants and optical affinities to microsomal cytochromes are determined for volatile chemicals under uncontrolled conditions.
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011312:Pressure; D011817:Rabbits; D014835:Volatilization
D006846:Hydrocarbons, Halogenated; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases