Interaction of chlormezanone with rat liver microsomes and its degradation

Abstract

Chlormezanone binds to oxidized cytochrome P450 in rat liver microsomes with a binding curve according to type I like hexobarbital but less pronounced and with a general shift to the left. Ethylmorphine N-demethylation, ethoxycoumarin and ethoxyresorufin O-deethylation are inhibited by chlormezanone in mM concentrations only whereas pentoxyresorufin O-depentylation is inhibited by about 50% in microM concentrations. Luminol and lucigenin amplified chemiluminescence indicating the formation of reactive oxygen species was not influenced in concentration ranges between mM and microM, 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 chlormezanone was elucidated. The first step involves ring opening by chemical hydrolysis with subsequent formation of an unstable acylhalfaminal which is the source of 4-chlorobenzaldehyde. This aldehyde undergoes enzymatically controlled oxidation to 4-chlorobenzoic acid which is the parent compound of following phase II reactions. The second degradation product is 2-carboxyethane-sulfinic-acid-N-methylamide, which is hydrolyzed very quickly. Neither oxidation of the sulfinic acid or its N-methylamide derivative could be observed nor N-demethylation of chlormezanone.

Interactions of melatonin with the liver microsomal cytochrome P450 system of rats and humans in vitro and effects on the P450 system and the antioxidative status in rat liver after acute treatment

“…Animals and biological materials: 60-12O-day-old male Han: Wist rats of the institute's own outbred stock were used, breeding and housing conditions cpo (5).Preparation of liver homogenate, 9000 g supernatant and microsomes cpo (5). Human liver 9000 g supernatant was prepared from the right lobe (64 years old female, resection of a colon carcinoma metastasis) immediately after operation and stored at -192°C, microsomes were prepared after thawing.…”

Investigations of Interactions of Chlormezanone Racemate and Its Enantiomers on Human Keratinocytes and Human Leucoytes in vitro

“…Klinger et al [15] observed that chlormezanone had no effect on zymosan-stimulated whole blood chemiluminescence. We used sedimented and IL-3 stimulated leukocytes and observed a significant decrease of ROS production at concentration of 1.0 mg/ml chlormezanone racemate or (-)-enantiomer.…”

Interaction of chlormezanone enantiomers with rat liver microsomes

“…Only weak interactions of racemic CM with the cytochrome P-450 system have been demonstrated in a previous paper (4). Inhibition of mono-oxygenase functions could be observed in high concentrations only.…”

“…All experiments are not influenced by the splitting of the S-C bond (2). However, the fate of this drug in the organism was successfully investigated only recently (3)(4)(5). According to these results, the S-C bond is split autoprotolytically, the participation of cytochrome P-450 could be excluded unequivocally.…”