Lung tumorigenesis promoted by anti-apoptotic effects of cotinine, a nicotine metabolite through activation of PI3K/Akt pathway.

We previously found that genetic polymorphism in cytochrome P450 2A6 (CYP2A6) is one of the potential determinants of tobacco-related lung cancer risk. It has been reported that the plasma concentration of cotinine, a major metabolite of nicotine, in carriers of wild-type alleles of CYP2A6 is considerably higher than that in carriers of null or reduced-function alleles of CYP2A6, raising the possibility that cotinine plays an important role in the development of lung cancer. As a novel mechanism of lung tumorigenesis mediated by CYP2A6, we investigated the effects of cotinine on the suppression of apoptosis and promotion of lung tumor growth.

Complex mechanism underlying transcriptional control of the haplotyped flavin-containing monooxygenase 3 (FMO3) gene in Japanese: different regulation between mutations in 5'-upstream distal region and common element in proximal region.

We reported the human flavin-containing monooxygenase 3 (FMO3) haplotypes (Pharmacogenet. Genomics: 17, 827, 2007). The objective was to gain the insight into transcriptional regulation in a Japanese population.

Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3).

Objectives: Flavin-containing monooxygenase 3 (FMO3) is involved in the metabolism of foreign chemicals, including therapeutic drugs, and thus mediates interactions between humans and their chemical environment. Loss-of-function mutations in the gene cause the inherited disorder trimethylaminuria, or fish-odour syndrome. The objective was to gain insights into the evolutionary history of FMO3.

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.

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.

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.

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.

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.

Two novel single nucleotide polymorphisms (SNPs) of the FMO3 gene in Japanese.

We sequenced all exons and exon-intron junctions of the flavin-containing monooxygenase 3 (FMO3) gene from 27 Japanese individuals who are trimethylaminuria volunteers judged by self-reported analysis. We found two novel single nucleotide polymorphisms (SNPs) (21246 T>A and 21265 C>T) causing amino acid substitutions (Asp(198)Glu and Arg(205)Cys in exon 5), respectively. The Asp(198)Glu allele also presented together with known SNPs (20852 C>T in exon4, 20960_20962 CTT deletion, 21115 G>A in intron 4, and 21243_21244 TG deletion in exon 5) in the same allele of the FMO3 gene to form a novel haplotype.

Two novel haplotypes of CYP2D6 gene in a Japanese population.

Two novel haplotypes of CYP2D6 were found in Japanese subjects. One haplotype of the human CYP2D6 gene, newly designated as CYP2D6(*)44 allele, had both a novel single nucleotide polymorphism (SNP) of 2950G>C in intron 6 donor splice junction and a known SNP (82C View Article and Find Full Text PDF

Novel nonsynonymous polymorphisms of the CYP1A1 gene in Japanese.

We found five novel nonsynonymous polymorphisms of the human CYP1A1 gene from Japanese individuals. The five single nucleotide polymorphisms (SNP) in exon 7 (2346_2347 ins T, 2414T>A, 2461C>T, 2500C>T and 2546C>G causing premature stop codon, Ile(448)Asn, Arg(464)Cys, and Arg(477)Trp and Pro(492)Arg, respectively) were as follows:SNP, 030212Saito001; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTCAACCCATCT-/TGAGTTCCTACCT-3'.SNP, 030212Saito002; GENE NAME, CYP1A1; ACCESSION NUMBER, X02612; LENGTH, 25 base; 5'-GTGAGAAGGTGAT/ATATCTTTGGCAT-3'.

Eighteen novel polymorphisms of the CYP2A13 gene in Japanese.

We sequenced all nine exons, exon-intron junctions including a part of introns, 5'-flanking and 3'-untranslated regions of the cytochrome P450 (CYP) 2A13 gene from 192 Japanese individuals. We found eighteen novel genetic polymorphisms including five single nucleotide polymorphisms (SNP) and one three base pair insertion causing amino acid substitution and one amino acid insertion, respectively, one silent SNP in exon 4, four SNPs in a 5'-flanking region, and seven SNPs in introns. The five SNPs (74G>A in exon 1, 579G>A in exon 2, 1706C>G in exon 3, and 7343T>A and 7465C>T in exon 9) causing amino acid substitutions (Arg(25)Gln, Arg(101)Gln, Asp(158)Glu, Phe(453)Tyr, and Arg(494)Cys), respectively.

Twenty one novel single nucleotide polymorphisms (SNPs) of the CYP2A6 gene in Japanese and Caucasians.

We sequenced all nine exons and exon-intron junctions of the CYP2A6 gene from 33 Japanese and 28 Caucasians. We found twenty one single nucleotide polymorphisms (SNPs) including four SNPs causing amino acid substitutions, one silent SNP in exon 5, one SNP in a 5'-flanking region, four SNPs in a 3'-untranslated region, and eleven SNPs in introns. The four mutations (13G>A and 86G>A in exon 1, and 2134A>G and 2161C>T in exon 4) causing amino acid substitutions (Gly(5)Arg, Ser(29)Asn, Lys(194)Glu, and Arg(203)Ser), respectively, were as follows: SNP, 020719Kiyotani004; GENE NAME, CYP2A6; ACCESSION NUMBER, NG_000008.

Novel mutations of the CYP2A6 gene in a Thai population with lowered capacity of coumarin 7-hydroxylation.

We explored genetic polymorphisms in a Thai population which exhibited a low capacity to metabolize coumarin. The following two silent single nucleotide polymorphisms (SNPs) were found: 1) SNP, 020228Kiyotani001; GENE NAME, CYP2A6; ACCESSION NUMBER, NT_011139; LENGTH, 25 base; 5'-AAACTACCTGCAG/TCTGAACACAGAG-3'. 2) SNP, 020228Kiyotani002; GENE NAME, CYP2A6; ACCESSION NUMBER, NT_011139; LENGTH, 25 base; 5'-AATCCCCAGCAC/TTTCCTGAATGAG-3'.

Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers.

We reported previously that subjects homozygous for the cytochrome P450 2A6 (CYP2A6) (*)4 have a lower risk of lung cancer. The purpose of this study was to clarify whether or not the alterations of smoking behavior and risk for lung cancer could be found in subjects possessing novel CYP2A6 variants discovered recently. An epidemiological study was performed with 1094 cases and 611 controls in male Japanese smokers.

Effects of the dietary supplements, activated charcoal and copper chlorophyllin, on urinary excretion of trimethylamine in Japanese trimethylaminuria patients.

Trimethylaminuria (TMAU) is a metabolic disorder characterized by the inability to oxidize and convert dietary-derived trimethylamine (TMA) to trimethylamine N-oxide (TMAO). This disorder has been relatively well-documented in European and North American populations, but no reports have appeared regarding patients in Japan. We identified seven Japanese individuals that showed a low metabolic capacity to convert TMA to its odorless metabolite, TMAO.

Identification of a novel polymorphic enhancer of the human CYP3A4 gene.

CYP3A4, the most abundant form of cytochrome P450 in the human adult liver, shows wide interindividual variation in its activity. This variability is thought to be caused largely by transcriptional and genetic factors, yet the underlying mechanisms are poorly understood. The purpose of this study was to clarify the mechanisms controlling the CYP3A4 gene transcription and to search for genetic polymorphisms in the 5'-flanking region of the CYP3A4 gene.

Decreased coumarin 7-hydroxylase activities and CYP2A6 expression levels in humans caused by genetic polymorphism in CYP2A6 promoter region (CYP2A6*9).

One of seven poor metabolizers of coumarin found in Thai subjects was previously genotyped as heterozygote for the CYP2A6*4 (whole deletion) and CYP2A6*9. Thus, we aimed to investigate the relationship between the genetic polymorphism in the TATA box of the CYP2A6 gene (CYP2A6*9), expression levels of CYP2A6 mRNA and coumarin 7-hydroxylase activities in human livers. Levels of CYP2A6 mRNA were quantified by real-time quantitative reverse transcriptase-polymerase chain reaction.

A population phenotyping study of three drug-metabolizing enzymes in Kyushu, Japan, with use of the caffeine test.

Objective: We assessed in vivo activities of cytochrome P450 1A2 (CYP1A2), N-acetyltransferase 2, and xanthine oxidase in Japanese residents of Kyushu, the southern island of Japan.

Methods: One hundred eighty-two healthy volunteers (108 men and 74 women) received a 150-mg oral dose of caffeine before they went to sleep. The concentrations of caffeine, caffeine metabolites, and uric acid in their overnight urine samples were analyzed.

[Genetic polymorphisms of drug metabolizing enzymes].

Multiple forms of CYP exist in humans. P450s comprise a superfamily of enzymes. These P450s play important roles in the oxidation of structurally diverse endobiotics and xenobiotic chemicals including anticancer drugs and carcinogens.

CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka.

We investigated the relationship between inter-individual difference in CYP2A6 genotype and susceptibility to oral cancer among habitual betel quid chewers in a Sri Lanka population. A total of 286 subjects showing oral malignant or premalignant lesions and 135 control subjects with no lesions were analyzed. The frequency of homozygotes for CYP2A6*4C mutation, a gene deletion type of polymorphism, was significantly lower in the case subjects than the controls.