In vitro metabolism and toxicity assessment of N-methylcarbazole in primary cultured rat hepatocytes.
N-Methycarbazole (NMC), a carcinogen and mutagen in tobacco smoke, was converted to two major metabolites by primary cultured rat hepatocytes as measured by high performance liquid chromatography (HPLC): N-hydroxymethylcarbazole (NHMC) and carbazole. These two metabolites had comparable retention times and identical ultraviolet spectra as those of reference standards. Identical retention times and mass spectra were also observed as detected by gas chromatography-mass spectroscopy (GC-MS) for NHMC and its reference standard. The toxicities of NMC and its two metabolites were assessed by lactate dehydrogenase (LDH) leakage and neutral red (NR) uptake. The rank order of cytotoxicity of NMC and its metabolites was found to be: NHMC greater than NMC greater than carbazole. Thus, we conclude that the hydroxylation of NMC to NHMC may represent a toxification step, while the further dealkylation to carbazole is most likely a detoxication process.
Yang
W
W
Department of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin 78712.
Jiang
T R
TR
Davis
P J
PJ
Acosta
D
D
D000818:Animals; D001711:Biotransformation; D002227:Carbazoles / Q000378:metabolism* / Q000633:toxicity*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D008658:Inactivation, Metabolic; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009499:Neutral Red; D051381:Rats
D002227:Carbazoles; C041514:carbazole; D009499:Neutral Red; C038545:N-methylcarbazole; D007770:L-Lactate Dehydrogenase