Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes.
Article Details
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Yamazaki H, Inoue K, Hashimoto M, Shimada T
Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes.
Arch Toxicol. 1999 Mar;73(2):65-70.
- PubMed ID
- 10350185 [ View in PubMed]
- Abstract
Nicotine C-oxidation by recombinant human cytochrome P450 (P450 or CYP) enzymes and by human liver microsomes was investigated using a convenient high-performance liquid chromatographic method. Experiments with recombinant human P450 enzymes in baculovirus systems, which co-express human nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH)-P450 reductase, revealed that CYP2A6 had the highest nicotine C-oxidation activities followed by CYP2B6 and CYP2D6; the Km values by these three P450 enzymes were determined to be 11.0, 105, and 132 microM, respectively, and the Vmax values to be 11.0, 8.2, and 8.6 nmol/min per nmol P450, respectively. CYP2E1, 2C19, 1A2, 2C8, 3A4, 2C9, and 1A1 catalysed nicotine C-oxidation only at high (500 microM) substrate concentration. CYP1B1, 2C18, 3A5, and 4A11 had no measurable activities even at 500 microM nicotine. In liver microsomes of 16 human samples, nicotine C-oxidation activities were correlated with CYP2A6 contents at 10 microM substrate concentration, whereas such correlation coefficients were decreased when the substrate concentration was increased to 500 microM. Contribution of CYP2B6 (as well as CYP2A6) was demonstrated by experiments with the effects of orphenadrine (and also coumarin and anti-CYP2A6) on the nicotine C-oxidation activities by human liver microsomes at 500 microM nicotine. CYP2D6 was found to have minor roles since quinidine did not inhibit microsomal nicotine C-oxidation at both 10 and 500 microM substrate concentrations. These results support the view that CYP2A6 has major roles for nicotine C-oxidation at lower substrate concentration and both CYP2A6 and 2B6 play roles at higher substrate concentrations in human liver microsomes.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Nicotine Cytochrome P450 1A1 Protein Humans UnknownSubstrateInducerDetails Nicotine Cytochrome P450 1A2 Protein Humans UnknownSubstrateInducerDetails Nicotine Cytochrome P450 2A6 Protein Humans UnknownSubstrateInhibitorDetails Nicotine Cytochrome P450 2B6 Protein Humans UnknownSubstrateDetails Nicotine Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Nicotine Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Nicotine Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Nicotine Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Nicotine Cytochrome P450 2E1 Protein Humans UnknownSubstrateInhibitorInducerDetails Nicotine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails