Metabolism and effect of para-toluene-sulfonamide on rat liver microsomal cytochrome P450 from in vivo and in vitro studies

Abstract

Aim: To study the in vivo and in vitro metabolism and the effect of para-toluenesulfonamide (PTS) on cytochrome P450 enzymes (CYP450). Methods: Total CYP450 and microsome protein content were determined after iv pretreatment of rats with PTS. CYP-specific substrates were incubated with rat liver microsomes. Specific CYP isoform activities were determined by using HPLC. CYP chemical inhibitors added to the incubation mixture were used to investigate the principal CYP isoforms involved in PTS metabolism. The effect of PTS on CYP isoforms was investigated by incubating PTS with specific substrates. Results: The groups treated with 33 and 99 mg/kg per d PTS, respectively, had a total CYP content of 0.66±0.17 and 0.60±0.12 nmol/mg. The K m and V max were 92.2 µmol/L and 0.0137 nmol/min per mg protein. CYP2C7, CYP2D1 and CYP3A2 might contribute to PTS metabolism in the rat liver. The inhibitory effects of sulfaphenazole and ketoconazole on PTS metabolism were shown to have a mixed mechanism, whereas PTS metabolism was inhibited noncompetitively by quinidine. PTS had little effect on the activities of the selected CYP isoforms. Conclusion: Generally speaking, it is relatively safe for PTS to be co-administered with other drugs. However, care should be taken when administering PTS with CYP inhibitors and the substrates of CYP2C, CYP2D and CYP3A.

Oxidative demethylenation and subsequent glucuronidation are the major metabolic pathways of berberine in rats

“…The effects of several human selective P450 inhibitors on the formation of the Phase I metabolites M1 and M2 in rat liver microsomes were investigated. The inhibitors used were: α‐naphthoflavone (for CYP1A),17 quinidine (for CYP2D1),18 orphenadrine (for CYP2B),19, 20 diethyldithiocarbamate (for CYP2E1),21 sulfaphenazole (for CYP2C6/11),22 and ketoconazole (for CYP3A1/2) 23. The concentrations used for BBR were 10, 50, and 200 µM and the concentrations of various inhibitors used were 2 and 10 µM for quinidine, 1 and 10 µM for α‐naphthoflavone, 10 and 50 µM for sulfaphenazole, 25 and 50 µM for orphenadrine, 12.5 and 25 µM for diethyldithiocarbamate, 1 and 10 µM for ketoconazole.…”

NTP Technical Report on the Toxicity Studies of p-Toluenesulfonamide (CAS No. 70-55-3) Administered in Feed to F344/N Rats, F344/NTac Rats, and B6C3F1/N Mice

“…Experiments in dogs suggested a similar metabolic pathway; 4-sulphamoylbenzoic acid was found in the urine of dogs given p-toluenesulfonamide 22 . Following intravenous administration of 33 or 198 mg/kg p-toluenesulfonamide to male Wistar rats for 4 days, total cytochrome P450 content in control and treated animals was similar 23 . The authors demonstrated that p-toluenesulfonamide metabolism is likely mediated through CYP2C7, CYP2D1, and CYP3A2.…”

Para-toluenesulfonamide induces tongue squamous cell carcinoma cell death through disturbing lysosomal stability

“…Measurement of intracellular PST by high-performance liquid chromatography (HPLC) was performed as described previously 9 . HPLC was performed using an Agilent 1100LC system (Agilent Technologies, Palo Alto, California, USA) equipped with a Zorbax C8 column (4.6×250 mm, 5 μm; Dupont, Wilmington, Delaware, USA).…”