INTERACTION OF CHLORMEZANONE WITH RAT-LIVER MICROSOMES AND ITS DEGRADATION

Chlormezanone binds to oxidized cytochrome P450 in rat liver microsome s with a binding curve according to type I like hexobarbital but less pronounced and with a general shift to the left, Ethylmorphine N-demet hylation, ethoxycoumarin and ethoxyresorufin O-deethylation are inhibi ted by chlormezanone in mM concentrations only whereas pentoxyresorufi n O-depentylation is inhibited by about 50% in mu M concentrations. Lu minol and lucigenin amplified chemiluminescence indicating the formati on of reactive oxygen species was not influenced in concentration rang es between mM and mu M, whereas NADPH/Fe stimulated lipid peroxidation showed a tendency of inhibition. But scavenger activity could not be demonstrated: the zymosan stimulated chemiluminescence of whole blood was not influenced significantly. The degradation process of chlormeza none was elucidated. The first step involves ring opening by chemical hydrolysis with subsequent formation of an unstable acylhalfaminal whi ch is the source of 4-chlorobenzaldehyde. This aldehyde undergoes enzy matically controlled oxidation to 4-chlorobenzoic acid which is the pa rent compound of following phase II reactions. The second degradation product is 2-carboxyethane-sulfinic-acid-N-methylamide, which is hydro lyzed very quickly. Neither oxidation of the sulfinic acid or its N-me thylamide derivative could be observed nor N-demethylation of chlormez anone.