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Biomedical subjects

Tetsuya Kamataki

Publications and source records attributed to Tetsuya Kamataki.

At least 19 recordsLinked to original sources
PubMed2006

Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia.

OBJECTIVE: This study investigated the relevance of the cytochrome P450 (CYP) 2D6 genotype to the adverse drug reactions (ADRs) of H1-antihistamines and the level of sedation. METHODS: Japanese participants in a health screening program were asked to describe any past history of ADRs. Any subjects reporting ADRs induced by H1-antihistamines were then individually interviewed and defined as cases. Excessive daytime sleepiness, which had occurred in the cases as an H1-antihistamine-induced ADR, was assessed by the Epworth sleepiness scale (ESS), and an ESS score >or=12 was considered hypersomnia. CYP2D6*4, *5, *14, and *10 were genotyped by a panel of polymerase chain reaction techniques. RESULTS: Out of 2,074 participants, 100 cases (M:F = 37:63, mean age 51.9 +/- 9.2 years) were eligible for analysis. The most common etiological drug was chlorpheniramine, which is the most frequently used H1-antihistamine in Japan. CYP2D6*10 allele and genotypes were more frequently found in the cases than in the healthy Japanese population in a large study (P < 0.005 and P = 0.039, respectively), but no difference was observed in the null alleles and genotypes. The ESS scores in 75 cases (M:F=25:50) who had experienced excessive daytime sleepiness were 9.5 +/- 5.5 in men and 12.9 +/- 6.1 in women (P < 0.001, cases vs. 34 subjects without symptoms; P = 0.001 men vs. women). The occurrence of hypersomnia increased as the number of CYP2D6 mutant alleles increased (P = 0.045). CONCLUSION: The results suggest that the presence of the CYP2D6*10 allele is a risk factor for development of H1-antihistamine-induced ADRs in Japanese.

Asian People↗
PubMed2006

Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population.

The reduced capacity of flavin-containing monooxygenase 3 (FMO3) to N-oxidize trimethylamine (TMA) is believed to cause a metabolic disorder. The aim of this study was to investigate the inter-individual variations of FMO3. Genomic DNA of case subjects that showed only 10-20% of FMO3 metabolic capacity among self-reported trimethylaminuria Japanese volunteers was sequenced. Functional analysis of recombinant FMO3 proteins was also performed. One homozygote for a novel single nucleotide substitution causing a stop codon at Arg500 was observed. The biological parents of this Proband A were heterozygous and showed >90% TMA N-oxygenation metabolic capacity. Another Proband B had the Arg500Stop and Cys197Stop codons. The TMA N-oxygenation metabolic capacities of the father and brother of this Proband B were apparently observed by possessing Arg205Cys mutant that coded for decreased TMA N-oxygenase. Recombinant Arg500Stop FMO3 cDNA expressed in Escherichia coli membranes and a series of highly purified truncation mutants at different positions of the C-terminus of FMO3 showed no detectable functional activity toward typical FMO3 substrates. The results suggest that individuals homozygous for either of the nonsense mutations, Arg500Stop and/or Cys197Stop alleles, in the FMO3 gene can possess abnormal TMA N-oxygenation.

Adolescent↗
PubMed2006

CYP2C76, a novel cytochrome P450 in cynomolgus monkey, is a major CYP2C in liver, metabolizing tolbutamide and testosterone.

Monkeys are widely used as a primate model to study drug metabolism because they generally show a metabolic pattern similar to humans. However, the paucity of information on cytochrome P450 (P450) genes has hampered a deep understanding of drug metabolism in the monkey. In this study, we report identification of the CYP2C76 cDNA newly identified in cynomolgus monkey and characterization of this CYP2C along with cynomolgus CYP2C20, CYP2C43, and CYP2C75. The CYP2C76 cDNA contains the open reading frame encoding a protein of 489 amino acids that are only approximately 80% identical to any human or monkey P450 cDNAs. Gene and protein expression of CYP2C76 was confirmed in the liver of cynomolgus and rhesus monkeys but not in humans or the great apes. Moreover, CYP2C76 is located at the end of the CYP2C gene cluster in the monkey genome, the region of which corresponds to the intergenic region adjacent to the CYP2C cluster in the human genome, strongly indicating that this gene does not have the ortholog in humans. Among the four CYP2C genes expressing predominantly in the liver, the expression level of CYP2C76 was the greatest, suggesting that CYP2C76 is a major CYP2C in the monkey liver. Assays for the capacity of CYP2C76 to metabolize drugs using several substrates typical for human CYP2Cs revealed that CYP2C76 showed unique metabolic activity. These results suggest that CYP2C76 contributes to overall drug-metabolizing activity in the monkey liver and might account for species difference occasionally seen in drug metabolism between monkeys and humans.

Amino Acid Sequence↗
PubMed2006

Dose dependent inhibitory effects of dietary 8-methoxypsoralen on NNK-induced lung tumorigenesis in female A/J mice.

We have reported that pretreatment by stomach tube with 8-methoxypsoralen (methoxsalen; 8-MOP), a potent human CYP2A6 inhibitor, strongly suppresses lung tumorigenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice (Cancer Res. 2003). Here, we examined inhibitory effects with administration in the diet. When the mice were 7 weeks of age, they received dietary supplementation with 8-MOP at concentrations of 1, 10 or 100 ppm for 3 days prior to a single dose of NNK (2mg/0.1 ml saline/mouse, i.p.) or an equal volume of saline (vehicle control). The experiment was terminated 16 weeks after the first 8-MOP treatment and lung proliferative lesions were analyzed. The incidences and multiplicities in the 8-MOP 100 ppm-treated group were significantly reduced as compared with values for the NNK alone group (P<0.001). Multiplicities of NNK-induced lung proliferative lesions were also reduced in a dose dependent manner (Spearman rank correlation coefficient; rho=-0.806, correction P<0.0001). Mouse CYP2A4 and CYP2A5 differ from each other only 11 amino acids, and are closely related to the human CYP2A6. One hour after the last of three daily doses of 8-MOP (0.5, 5 or 50mg/kg body weight in 0.2 ml corn oil, given by stomach tube) or an equal volume of corn oil (vehicle control), given to the mice at 7 weeks of age, isolation of lung and liver RNAs demonstrated no effects on CYP2A4 and CYP2A5 mRNA levels with 8-MOP. In conclusion, the results of this study showed that clear dose response inhibitory effects of 8-MOP on NNK-induced lung tumorigenesis in female A/J mice fed diets containing 8-MOP, due to inhibition of enzyme activity of CYP2A4 and CYP2A5, rather than their gene expression.

Administration, Oral↗
PubMed2006

Activation of p53 as a causal step for atherosclerosis induced by polycyclic aromatic hydrocarbons.

This study was performed to prove our hypothesis that the metabolite(s) of polycyclic aromatic hydrocarbons (PAHs) caused the activation or phosphorylation of p53 via DNA damage to suppress the liver X receptor (LXR)-mediated signal transductions as a probably more direct mechanism. We found that LXR-mediated trans-activation was inhibited by 3-methylchoranthrene (MC) and doxorubicin (Dox) in HepG2 cells carrying wild-type p53, but not in Hep3B cells possessing mutant p53. The exogenous expression of wild-type p53 suppressed the LXR-mediated trans-activation in Hep3B cells. The expression of mRNA for ATP binding cassette A1 was suppressed by MC and Dox in HepG2 cells. The protein expression of retinoid X receptor (RXR), a partner of LXR to form a heterodimer, was suppressed by MC and Dox in HepG2 cells.

Antibiotics, Antineoplastic↗
PubMed2006

Comparative cytochrome P450 -1A1, -2A6, -2B6, -2C, -2D6, -2E1, -3A5 and -4B1 expressions in human larynx tissue analysed at mRNA level.

The metabolic activation of numerous exogenous and endogenous chemicals is catalysed by cytochrome P450 enzymes (CYPs). The aim of this study was to analyse the expression of the individual forms of CYP at the mRNA level in human larynx and quantitatively to compare their expressions in human liver, the main organ of CYP expression. Individual forms of CYP mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) using specific primers for the CYPs -1A1, -1A2, -2A6, -2B6, -2C, -2D6, -2E1, -3A3/4, -3A5, -3A7 and -4B1. An RNA competitor of known copy number, covering the primer sequences necessary to amplify the entire object CYPs within a single molecule, was used as reference. This study reports a consistent detection of mRNAs for the CYPs -1A1, -2A6, -2B6, -2C, -2D6, -2E1, -3A5 and -4B1 in the human larynx tissue. The data indicate that the human larynx highly resembles the lung tissue in CYP content, as a comparable subset of CYP mRNAs was detected in the larynx previously reported for human lung with the exception of CYP1A2. The results are discussed in quantitative ratios of the detected CYP mRNAs in relation to the hepatic CYP expression.

Aryl Hydrocarbon Hydroxylases↗
PubMed2006

[How I was enticed into molecular toxicology].

This paper introduces one of our projects performed at Hokkaido University. During the course of pharmacokinetic studies of SM-12502, which was under development as an anti-platelet-activating factor agent, we found three individuals who showed a slow metabolic phenotype in its pharmacokinetics. Analyzing the genes for CYP2A6 from the three, we discovered that they had the whole CYP2A6 gene deletion (CYP2A6*4C). Genetically engineered Salmonella YG7108 cells expressing human P450 were established to compare the mutagen-producing capacity of the P450 enzymes for various N-nitrosamines. We found that CYP2A6 was involved in the metabolic activation of N-nitrosamines with relatively bulky alkyl chains such as a tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which has been known to cause lung tumors in rodents. Thus, to examine the hypothesis that individuals possessing the CYP2A6*4C have a reduced risk of cancer due to the lack of the metabolic activation of certain carcinogens in tobacco smoke, a case-control study was performed. The results clearly indicated a significant association between the CYP2A6 genotype and lung cancer risk in smokers. In contrast, there was no significant relationship between them in nonsmokers. In addition, our results showed that the reduced risk of cancer was caused by the reduced activity of CYP2A6. Thus it was expected that the inhibition of the enzyme would result in a reduced cancer risk caused by smoking. The results of experiments using mice which were treated with NNK, a carcinogenic nitrosamine contained in tobacco smoke, together with 8-methoxypsolaren, a strong inhibitor of CYP2A6, indicated that the inhibition of CYP2A6 completely abolished the occurrence of adenoma.

Animals↗
PubMed2006

In vivo evaluation of coumarin and nicotine as probe drugs to predict the metabolic capacity of CYP2A6 due to genetic polymorphism in Thais.

The association between the distribution characteristics of CYP2A6 catalytic activities toward nicotine and coumarin, and the frequency distribution of CYP2A6 variant alleles reported was estimated in 120 healthy Thais. The distributions of the subjects as classified by the amounts of 7-hydroxycoumarin (7-OHC) excreted in the urine and by cotinine/nicotine ratio in the plasma were clearly bimodal. However, the numbers of apparently poor metabolizers for coumarin and nicotine were different. The inter-individual variability in the in vivo dispositions of coumarin and nicotine closely related to the CYP2A6 genetic polymorphism. There was a close correlation between the rate of 7-OHC excretion in the urine and cotinine/nicotine ratio in the plasma among subjects (R=0.92, p<0.001). The frequency of CYP2A6 allele found in the present study was: CYP2A6*1A=32% (95% CI, 22.1-39.4%), CYP2A6*1B=27% (95% CI, 19.4-33.5%), CYP2A6*9=20% (95% CI, 17.6-23.3%), CYP2A6*4=14% (95% CI, 9.6-17.8%), CYP2A6*7=5% (95% CI, 3.7-9.4%), CYP2A6*10=2% (95% CI, 0.8-5.1%). Subjects having CYP2A6*1A/*1B were found to have a higher rate of 7-OHC excretion, as well as a higher cotinine/nicotine ratio in the plasma compared with those of the other genotypes. In contrast, subjects with CYP2A6*4/*7 and CYP2A6*7/*7 almost lacked any cotinine formation, whereas urinary 7-OHC was still detectable. CYP2A6*9 allele clearly resulted in reduced enzyme activities. Despite the absence of the homozygote for CYP2A6*10 allele, the presence of CYP2A6*10 allele significantly decreased the enzyme activities. The results of the present study demonstrate that in vivo phenotyping of CYP2A6 using nicotine and coumarin are not metabolically equivalent. Nicotine is a better probe according to its specificity, while coumarin is still valuable to be used for a routine CYP2A6 phenotyping since the test employs a non-invasive method.

Administration, Oral↗
PubMed2005

CYP1A1-mediated mechanism for atherosclerosis induced by polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) have been known to induce atherosclerosis. It has been reported that the metabolic activation of PAHs by cytochrome P450 (CYP) is an important step for PAH-induced atherosclerosis. We recently reported that PAHs down-regulated the liver X receptor (LXR) alpha-regulated genes via aryl hydrocarbon receptor (AHR) as one of the causes responsible for atherosclerosis induced by PAHs. Thus, the aim of this study was to clarify the role of CYP1A1 in the suppression of LXR-mediated signal transductions by 3-methlychoranthrene (MC), one of the PAHs. We found that LXR-mediated transactivation was inhibited by the PAH, but not by halogenated aromatic hydrocarbon, which is scarcely metabolized by CYP1A1. The repression of LXR-mediated signal transductions by MC was restored by co-treatment of HepG2 cells with a CYP1A1 inhibitor, alpha-naphthoflavone, and by the transfection of short interference RNA for CYP1A1. Based on these lines of evidence, we propose that the metabolic activation of PAHs by CYP1A1, but not the activation of AHR by PAHs, is a direct mechanism for atherosclerosis via the suppression of LXR-mediated signal transductions.

Animals↗
PubMed2005

A possible mechanism for atherosclerosis induced by polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs), aryl hydrocarbon receptor (AHR) ligands, induce atherogenesis. Liver X receptor (LXR) alpha is known to be involved in the control of cholesterol homeostasis. Thus, the purpose of this study was to investigate the effects of 3-methlycholanthrene (MC), one of the PAHs, on LXRalpha-mediated signal transductions. We found that expression of mRNAs for ATP binding cassette A1, sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase, and stearoyl-CoA desaturase was suppressed by treatment of HepG2 cells with MC. A luciferase reporter assay revealed that LXRalpha- and SREBP-1c-mediated transactivations were inhibited by MC via AHR. Based on these lines of evidence, we propose that down-regulation of the LXRalpha-regulated genes by PAHs is one of the causes responsible for atherosclerosis induced by PAHs.

Arteriosclerosis↗
PubMed2005

Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk.

Analyzing the CYP2A6 gene of subjects who showed a poor metabolic phenotype toward SM-12502, we discovered a novel mutant allele (CYP2A6*4C) lacking the whole CYP2A6 gene. Using genetically engineered Salmonella typhimurium expressing a human CYP, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke. Taking these results into consideration, we hypothesized that the subjects carrying the CYP2A6*4C allele had lower risk of tobacco-related lung cancer. In accordance with our hypothesis, our epidemiological studies indicated that smokers homozygous for the CYP2A6*4C allele showed much lower odds ratios toward cancer risk. Other mutant alleles reducing the CYP2A6 activity, besides CYP2A6*4C, also reduced the risk of lung cancer in smokers, particularly of squamous-cell carcinoma and small-cell carcinoma, both smoking-related cancers. 8-Methoxypsoralen, an inhibitor of CYP2A6, efficiently prevented the occurrence of adenoma caused by NNK in A/J mice.

Animals↗
PubMed2005

Cyp2a6 is a principal enzyme involved in hydroxylation of 1,7-dimethylxanthine, a main caffeine metabolite, in humans.

In a caffeine test previously performed with healthy Japanese volunteers, we found that the CYP1A2 index defined as urinary {5-acetylamino-6-amine-3-methyluracil (AAMU)+1-methylxanthine (1X)+1-methyluric acid (1 U)}/1,7-dimethyluric acid (17 U) was affected by the whole deleted allele of CYP2A6 (CYP2A6*4). Since the high value of the CYP1A2 index could be caused by a low urinary concentration of 17 U, we postulated that CYP2A6 was responsible for the 1,7-dimethylxanthine (17 X) metabolism to generate 17 U (17 X 8-hydroxylation). Thus, the role of CYP2A6 in the 17 X 8-hydroxylation was fully examined in the present study. Among 10 isoforms of human cytochrome P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, or CYP3A5) expressed in Escherichia coli cells, CYP2A6 and CYP1A2 showed high catalytic activities for the 17 X 8-hydroxylation. The 17 X 8-hydroxylase activities significantly associated with coumarin 7-hydroxylase activities (r=0.67, p<0.01) in liver microsomes from 17 individuals, but not with ethoxyresorufin O-deethylase activities. Tranylcypromine, an inhibitor of CYP2A6, reduced the 17 X 8-hydroxylase activities of human liver microsomes. The 17 X 8-hydroxylase activities of CYP2A6.7, CYP2A6.10, and CYP2A6.11 expressed in E. coli cells were 12, 13, and 22% of that of CYP2A6.1, respectively. The 17 X 8-hydroxylase activities were found to be low in liver microsomes from individuals possessing the deletion or mutations in the CYP2A6 gene. Based on these data, we conclude that CYP2A6 is a main 17 X 8-hydroxylase and that the catalytic activities for the 17 X 8-hydroxylation are reduced by the genetic polymorphisms of the CYP2A6 gene.

Adult↗
PubMed2005

Mechanisms of chemopreventive effects of 8-methoxypsoralen against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung adenomas.

Recently we reported that the occurrence of lung adenoma caused by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was completely prevented by pretreatment of female A/J mice with 8-methoxypsoralen, a potent inhibitor of cytochrome P450 (P450 or CYP) 2A [Takeuchi et al. (2003) Cancer Res., 63, 7581-7583]. Thus, the aim of this study was to confirm that 8-methoxypsoralen exhibits chemopreventive effects by inhibiting CYP2A in the mouse lung. The involvement of CYP2A in the metabolic activation of NNK in the lung was first evidenced by the fact that the mutagenic activation of NNK by mouse lung microsomes was inhibited by 8-methoxypsoralen, coumarin and antibodies to rat CYP2A1. Supporting this, the mutagenic activation of NNK was efficiently catalyzed by mouse CYP2A4 and CYP2A5 co-expressed with NADPH-P450 reductase in a genetically engineered Salmonella typhimurium YG7108. The expression of mRNA for CYP2A5, but not for CYP2A4 or CYP2A12, in the mouse lung was proven by reverse transcriptase-polymerase chain reaction, probably indicating that CYP2A5 present in the mouse lung was involved in the metabolic activation of NNK. In accordance with these in vitro data, treatment of gpt delta transgenic mice with 8-methoxypsoralen prior to NNK completely inhibited the mutation of the gpt delta gene. The in vivo chemopreventive effects of 8-methoxypsoralen towards NNK-induced adenoma was seen only when the agent was given to female A/J mice prior to, but not posterior to, NNK, lending support to the idea that NNK is activated by CYP2A5 in the mouse lung as an initial step to cause adenoma. The inhibition by 8-methoxypsoralen of NNK-induced adenoma was seen in a dose-dependent manner: the dose to show apparent 50% suppression was calculated to be 1.0 mg/kg. To our surprise, CYP2A protein(s) was expressed in the lesion of NNK-induced lung adenomas, probably suggesting that 8-methoxypsoralen could inhibit the possible occurrence of further mutation of the adenoma cells induced by NNK. Based on these lines of evidence, we propose that 8-methoxypsoralen inhibits the CYP2A5-mediated metabolic activation of NNK in the mouse lung, leading to the prevention of NNK-induced adenoma.

Adenoma↗
PubMed2005

High prevalence of cytochrome P450 2A6*1A alleles in a black African population of Ghana.

OBJECTIVE: We investigated the frequencies of the functionally important variants of the CYP2A6 gene in black African populations. METHODS: Using genomic DNA sequencing, polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR, the allele frequencies of CYP2A6 *1A, *1B, *2, *4A, *5, *6, *7, *8, *9, *10 and * 11 among 120 black Africans- including 105 Ghanaians, 12 Nigerians, 2 Ivorians and 1 Ugandan-were determined. RESULTS: The allele frequencies were 80.5% for CYP2A6*1A, 11.9% for CYP2A6*1B, 1.9% for CYP2A6*4A and 5.7% for CYP2A6*9 in the Ghanaian subjects. No subject homozygous for the CYP2A6*4A allele, a whole gene deletion type of polymorphism prevalent among Orientals, was found. Furthermore, CYP2A6 variants such as *2, *5, *6, *7, *8, *10 and *11 were absent in these black African populations. CONCLUSIONS: This study provides, for the first time, the results of the analysis of CYP2A6 allele frequency in black African populations and confirms large ethnic differences in the polymorphic CYP2A6 gene.

Adult↗
PubMed2005

Novel gender-related regulation of CYP2C12 gene expression in rats.

The expression of CYP2C12 by GH occurs in female but not in male rat livers. Direct injection of the CYP2C12 promoter-luciferase gene into male rat livers showed that the CYP2C12 promoter was active in both male and female rats. Thus, to further examine one or more factors that regulate the gender-related expression of CYP2C12, male rats were treated with trichostatin A, a specific inhibitor of histone deacetylase capable of condensing the chromatin structure. Interestingly, the expression of CYP2C12 by GH was seen even in the livers of male rats, indicating that histone deacetylase contributes to the suppression of CYP2C12 expression in male rats. Deoxyribonuclease I hypersensitive assay using nuclei from the livers of male or female rats revealed that the chromatin structure of the CYP2C12 gene was gender specific: a hypersensitive site at a position -4.2 kb containing GH-responsive element that bound to signal transducer and activator of transcription 5 (STAT5), termed as HS (hypersensitive site) 1, was specific for female rat livers, whereas a hypersensitive site at a position -3 kb, designated as HSm (male-specific hypersensitive site), was characteristic of male rat livers. A -3425/-3275 region within HSm functioned as a negative regulatory region, when the region was inserted in front of simian virus 40 promoter. Gel shift assay demonstrated that both CCAAT/enhancer-binding protein alpha and beta bound to the -3425/-3275 region. Based on these results, we conclude that the gender-related expression of the CYP2C12 gene results from the inaccessibility of to STAT5 to the GH-responsive element by chromatin condensation seen in male rat livers, and from the presence of the male-specific HSm that acts as a silencer.

5' Flanking Region↗
PubMed2005

Mutagenic activation of betel quid-specific N-nitrosamines catalyzed by human cytochrome P450 coexpressed with NADPH-cytochrome P450 reductase in Salmonella typhimurium YG7108.

Betel quid chewing is known to cause cheek cancer in a wide area covering Africa to Asia. Areca nut contained in the betel quid is believed to give rise to carcinogenic N-nitrosamines. In the present study, the roles of human cytochromes P450 (P450 or CYP) in the mutagenic activation of betel quid-specific N-nitrosamines such as 3-(N-nitrosomethylamino)propionitrile (NMPN), 3-(N-nitrosomethylamino)propionaldehyde (NMPA) and N-nitrosoguvacoline (NG) were examined by using genetically engineered Salmonella typhimurium YG7108 expressing each form of human P450 together with NADPH-P450 reductase, which had been established in our laboratory. Among typical P450s (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2D6 or CYP3A4) examined, CYP2A6 was the most efficient activator of NMPN, followed by CYP1A1 and CYP1B1. The mutagenic activation of NMPN by CYP2A6 was seen at the substrate concentrations of microM levels (approximately 100 microM). The activation of NMPA was catalyzed predominantly by CYP2A13 and to lesser extents by CYP2A6, CYP1A1, CYP1A2 and CYP1B1. The activation of NMPA by CYP2A13 was detectable at the substrate concentrations of microM levels (approximately 1 microM). NG was activated by CYP2A13 and CYP2A6, the genotoxicity of NG being much lower than that of NMPA or NMPN. Based on these data, we conclude that human CYP2A subfamily members play important roles in the mutagenic activation of essentially all betel quid-related N-nitrosamines tested in the present study.

Animals↗
PubMed2005

Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human liver microsomes.

To anticipate drug-drug interactions by nicardipine in vivo, cytochrome P450 (CYP) forms responsible for the metabolism of nicardipine and inhibition of CYP-dependent drug metabolism by nicardipine were investigated. Microsomes of human B-lymphoblastoid cells expressing each human CYP form were used for the metabolism of nicardipine. Inhibitory effects of nicardipine on drug metabolism were studied using human liver microsomes. CYP2C8, CYP2D6 and CYP3A4 were identified as major CYP forms for the metabolism of nicardipine in human liver microsomes. Nicardipine strongly inhibited two-pathways of triazolam hydroxylation both catalyzed by CYP3A4. Comparison of three Ca(2+) antagonists, nicardipine, nifedipine, and diltiazem revealed that only nicardipine showed such a strong inhibitory potency on the typical CYP2D6-catalyzed drug metabolism. Furthermore, nicardipine inhibited other reactions catalyzed by CYP1A, CYP2A6, CYP2C8, CYP2C9 and CYP2C19 with K(i) values ranging from 1.1 to 29.4 microM. In conclusion, nicardipine was a relatively potent inhibitor of human CYP2D6, CYP3A4 and CYP2C (especially for CYP2C8 and CYP2C19) in vitro, suggesting that drug-drug interactions between nicardipine and other drugs metabolized mainly by these CYP forms appear to occur in vivo.

Cell Line↗