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Biomedical subjects

K Nakachi

Publications and source records attributed to K Nakachi.

At least 19 recordsLinked to original sources
PubMed1996

Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer.

We reported an association of smoking-induced lung cancer susceptibility with the human cytochrome P450 1A1 (CYP1A1) polymorphisms in our previous studies. To investigate a relationship between genetically determined individual predispositions and mutations of target genes in the early stage of lung carcinogenesis, we examined p53 mutations in relation to germ line polymorphisms of the CYP1A1 and GSTM1 genes, using surgical specimens of 148 non-small cell lung cancer patients who were smokers. The frequency of p53 mutations among heavy smokers was higher than in patients who had never smoked [P < 0.01; odds ratio (OR), 3.74; 95% confidence interval (CI), 1.46-9.56]. By single-strand conformational polymorphism, aberrant migration bands of p53 gene fragments were detected in 56 cases (38%). Smokers with susceptible rare homozygous alleles of either the MspI or Ile-Val polymorphism of the CYP1A1 gene have a 4.5-fold (P < 0.005; OR, 4.48; 95% CI, 1.64-12.26) or 5.5-fold (P < 0.01; OR, 5.52; 95% CI, 1.55-19.64) higher risk of having a mutation of the p53 gene than those with nonsusceptible predominant homozygous alleles of the gene. Non-small cell lung cancer patients with a susceptible CYP1A1 genotype were at remarkably high risk of having a mutation of the p53 gene when the genotype was combined with a deficient genotype, GSTM1(-). However, there was no difference between the types of p53 mutation and genotypes of the drug-metabolizing enzymes. These results showed that CYP1A1 germ line polymorphisms, which were associated with the genetic predisposition for lung cancer, were related to cigarette smoking-associated p53 mutations.

Cytochrome P-450 Enzyme System↗
PubMed1995

Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases.

OBJECTIVE: To investigate the association between consumption of green tea and various serum markers in a Japanese population, with special reference to preventive effects of green tea against cardiovascular disease and disorders of the liver. DESIGN: Cross sectional study. SETTING: Yoshimi, Japan. SUBJECTS: 1371 men aged over 40 years resident in Yoshimi and surveyed on their living habits including daily consumption of green tea. Their peripheral blood samples were subjected to several biochemical assays. RESULTS: Increased consumption of green tea was associated with decreased serum concentrations of total cholesterol (P for trend < 0.001) and triglyceride (P for trend = 0.02) and an increased proportion of high density lipoprotein cholesterol together with a decreased proportion of low and very low lipoprotein cholesterols (P for trend = 0.02), which resulted in a decreased atherogenic index (P for trend = 0.02). Moreover, increased consumption of green tea, especially more than 10 cups a day, was related to decreased concentrations of hepatological markers in serum, aspartate aminotransferase (P for trend = 0.06), alanine transferase (P for trend = 0.07), and ferritin (P for trend = 0.02). CONCLUSION: The inverse association between consumption of green tea and various serum markers shows that green tea may act protectively against cardiovascular disease and disorders of the liver.

Adult↗
PubMed1995

Association of cigarette smoking and CYP1A1 polymorphisms with adenocarcinoma of the lung by grades of differentiation.

We have previously reported on an association of genetic susceptibility to squamous cell carcinoma of the lung with two polymorphisms of the CYP1A1 gene, an MspI polymorphism and an isoleucine-valine (Ile-Val) polymorphism. We report here that the two CYP1A1 polymorphisms were associated with current or ex-smokers with adenocarcinoma of the lung. We first compared smoking status of the patients by differentiation grades of adenocarcinoma. Proportion of current or ex-smokers and their cigarette consumption was the highest among the poorly differentiated. Second, the two polymorphisms of CYP1A1 were examined among current or ex-smokers with three differentiation grades, and we found that poorly differentiated adenocarcinoma showed significantly high frequencies of genotypes C and Val/Val, which have been found to be 'susceptible' in squamous cell carcinoma of the lung. Third, a case-control study was carried out to estimate the genetic risk for CYP1A1 genotypes to differentiation grades, selecting only current or ex-smokers in patients and controls. Current or ex-smokers with 'susceptible' genotype C or Val/Val were at significant risk, with an odds ratio of 3.25 or 3.22 (95% confidence interval (CI), 1.40-7.56 or 1.00-10.32) for adenocarcinoma as a whole, respectively. The odds ratio increased to 4.51 or 4.09 (95% CI, 1.73-11.78 or 1.12-14.91) for poorly differentiated, while the odds ratios for other differentiated grades were not significant. Finally, a relation of the genetic risk to cigarette dose levels was evaluated.

Adenocarcinoma↗
PubMed1995

Polymorphisms of human Ah receptor gene are not involved in lung cancer.

The Ah receptor (Ahr) is a ligand-dependent transcription factor that positively regulates inducible expression of the CYP1A1 gene. Based on the sequence information of the human Ahr and the intron-exon junctions of the mouse counterpart, an analysis of single-strand conformational polymorphism (SSCP) was carried out to detect subtle base differences in the coding region of the gene among individuals. We found that the Ahr protein has at least two forms of variants in a Japanese gene pool, and that these variants can be ascribed to one amino acid replacement of Arg by Lys at codon 554. The frequencies of Arg-coded and Lys-coded alleles were 0.57 and 0.43, respectively. We found, however, that this germ line polymorphism of the Ahr gene did not show a significant association with aryl hydrocarbon hydroxylase (AHH) inducibility nor with lung cancer incidence.

Animals↗
PubMed1995

An Rsa I polymorphism in the CYP2E1 gene does not affect lung cancer risk in a Japanese population.

CYP2E1 catalyzes the metabolic activation of tobacco-specific N-nitrosamines, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. An Rsa I polymorphism, which is located in the 5'-flanking region of the CYP2E1 gene, has been found to affect the transcriptional regulation of the gene, resulting in different expression levels of the mRNA among individuals. In order to investigate an association between the Rsa I polymorphism and lung cancer susceptibility, the genotype distribution among 316 lung cancer patients was compared with that in 503 healthy controls. No statistically significant association was found between the Rsa I polymorphism and an increased risk of lung cancer, even though histological types of lung cancer, cigarette smoking and alcohol consumption were taken into account.

Cytochrome P-450 CYP2E1↗
PubMed1994

Interindividual difference in expression of human Ah receptor and related P450 genes.

The genomic clones of human aryl hydrocarbon receptor (Ahr) and Ahr nuclear translocator (Arnt) were isolated, and the structures of exon-intron junctions of these genes were partially determined. Based on the sequence information, a quantitative RT-PCR analysis was developed, and the expression of these genes was studied in various human tissues. mRNAs for Ahr and Arnt were widely expressed in human tissues and abundantly in lung. Individual difference in expression levels of Ahr and Arnt mRNA was observed in liver, lung and blood. In order to examine whether expression levels of Ahr and Arnt were associated with those of CYP1A1, we studied the expression of these mRNAs in blood among 20 healthy subjects, taking account of individuals' cigarette smoking habits. We found that the expression levels of CYP1A1 appeared to associate with those of Ahr and Arnt mRNAs (P < 0.06), and also that the expression of Ahr and Arnt was influenced by cigarette smoking. The expression of human Ahr and Arnt is reported here for the first time, providing a quantitative RT-PCR analysis as a useful tool for further studies.

Adult↗
PubMed1993

Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population.

An association of lung cancer susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene was reported in our previous study. This polymorphism has been subsequently found to be closely linked to another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of P4501A1. We report here that genetic risk for squamous cell carcinoma of the lung was associated with these two polymorphisms of the CYP1A1 gene in terms of genotype frequencies and cigarette-smoking dose and that a more increased risk was observed for the individuals with "susceptible" genotypes of CYP1A1 combined with a deficient genotype of a mu-class glutathione S-transferase (GST1), which detoxifies the electrophilic metabolites of aromatic hydrocarbon procarcinogens activated by P4501A1. We first compared the total amounts of cigarettes consumed during a lifetime among 85 patients with squamous cell carcinoma of the lung, whose CYP1A1 and GST1 genes were identified. The patients with a susceptible homozygote of each of the MspI and Ile-Val polymorphisms contracted the carcinoma after smoking fewer cigarettes than those with other genotypes. When the GST1 polymorphism was taken into account, the cumulative cigarette amounts in combined genotyping of the two genes showed distinct differences, resulting in the lowest cigarette dose observed for the patients with a susceptible MspI or Ile-Val genotype of CYP1A1 combined with a deficient GST1 homozygote. Next, a case-control study revealed that the individuals with the susceptible MspI or Ile-Val genotype combined with deficient GST1 were at remarkably high risk with an odds ratio of 16.00 or 41.00, respectively (95% confidence interval, 3.76-68.02 or 8.68-193.61, respectively), at a low dose level of cigarette smoking.

Adult↗
PubMed1993

The CYP1A1 gene and cancer susceptibility.

A close correlation between cigarette smoking associated lung cancer incidence and an Msp I restriction fragment length polymorphism (RFLP) of the human P-450 1A1 (CYP1A1) gene was found in a Japanese population in terms of genotype frequency and cigarette dose. A Val/Ile codon difference in the primary structure of the CYP1A1 protein (Val-, Ile-type) was in linkage disequilibrium with the Msp I RFLP. A synergistic increase in susceptibility to lung cancer was found when combining genotyping of CYP1A1 and the Mu-class of glutathione S-transferase (GST1). Interindividual variability in the genetic make-up of carcinogen metabolizing enzymes may thus be a key host factor to explain the differences in susceptibility to chemical carcinogenesis among individuals.

Cytochrome P-450 Enzyme System↗
PubMed1993

Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer.

The p53 tumor suppressor gene is mutated in diverse types of human cancer, and the normal allele encodes a nuclear protein that regulates expression of cell cycle-related genes as a transcription factor. The wild-type of p53 protein exists as at least two forms of variants among human populations, ascribed to amino acid replacement at codon 72 of Arg by Pro. In this study, we show that this germ line Arg-Pro polymorphism at codon 72 of the p53 gene is associated with genetically determined susceptibility to smoking-induced lung cancer; a susceptible genotype Pro/Pro has a 1.7-fold higher risk of this cancer compared with other genotypes. This p53 polymorphism modulates risk to smoking-induced lung cancer independently of other genetic risk factors such as germ line polymorphism of CYP1A1 or GST1 genes.

Adenocarcinoma↗
PubMed1992

Esophageal cancer in Shanxi Province, People's Republic of China: a case-control study in high and moderate risk areas.

Dietary, smoking, and drinking habits, as well as sociopsychological factors and familial history, were investigated in a case-control study on the etiology of esophageal cancer (EC) in two areas of Shanxi (Yangcheng and Linfen), north central China. Data were analyzed from 326 cases and 396 controls. We identified several factors associated with high or low risk; some were common across the areas and others were area-specific. Consumption of millet gruel was associated positively with EC, in a dose-response relationship. An increase in EC risk was seen for consumption of millet soup with noodles, and also with certain sociopsychological factors, in both areas. A large increase in risk was found with consumption of boiled vegetables in Linfen, with a dose-response relationship. EC risk tended to become greater with the increasing intake of moldy foods and of pickled vegetable juice. A positive association between EC risk and family history of EC was observed only in Yangcheng. Soybean consumption was found to be associated with reduced risk. Dental hygiene (brushing teeth) was associated with reduced risk in Linfen. There was a suggestion of increased risk associated with heavy tobacco smoking, but it was not significant in either area. Alcohol consumption had a marginally significant association with risk in the high risk area, but not in Linfen.

Adult↗
PubMed1992

Environmental and physiological influences on human natural killer cell activity in relation to good health practices.

We examined the association of natural killer (NK) cell activity with a number of life style factors by a cross-sectional analysis on 2892 Japanese individuals. The following habits were found to be associated with increased NK activity: 1) alcohol drinking (males, P less than 0.05), 2) not smoking cigarettes (males and females, P less than 0.001), 3) increased intake of green vegetables (females, P less than 0.001), 4) increased intakes of meat, milk, dairy products, and soybean products (males, P less than 0.01), 5) daily workload of less than 3 hours per day (females, P less than 0.05), 6) regular meals (females, P less than 0.05), 7) regular sleep of more than 7 hours (females, P less than 0.05), 8) proper body weight. In addition, systolic blood pressure showed a positive correlation with NK activity (P less than 0.001), while proportion of helper/inducer (OKT4+) T cells and fraction of beta-globulin showed negative correlations (P less than 0.001). We thus found that the living habits associated with increased NK activity were consistent with generally accepted good health practices, except alcohol drinking.

Adult↗
PubMed1991

Genetic susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose.

Cytochrome P450IA1 is responsible for the metabolic activation of benzo(a)pyrene in cigarette smoke; an association of lung cancer with DNA polymorphisms of P450IA1 gene was shown in our previous study. In this paper, we investigated the interindividual difference of genetically determined susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose. We first compared the total amounts of cigarettes consumed over the lifetime of patients and showed that the patients with a "susceptible" P450IA1 gene genotype contracted carcinoma after fewer cigarettes [mean +/- SD, 31.3 +/- 12.8 x 10(4) cigarettes (n = 12)] than those with other genotypes [42.5 +/- 18.2 x 10(4) (n = 33)], with a statistical significance of P less than 0.05. Next, we carried out a case-control study to estimate the odds ratios of susceptible to nonsusceptible individuals in relation to the cumulated cigarette dose. We thus showed that the individuals with the susceptible genotype were at remarkably high risk with an odds ratio of 7.31 (95% confidence interval, 2.13 to 25.12) at a low dose level of cigarette smoking and that the difference in susceptibility between genotypes was reduced at high dose levels.

Adenocarcinoma↗
PubMed1991

Genetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene.

Individuals with high genetic risk of lung cancer had previously been identified by MspI polymorphisms of the cytochrome P450IA1 gene. In the present study we analyzed the structures of individual P450IA1 genes by PCR direct sequencing of genomic DNA of each genotype raised by the MspI polymorphisms, which were ascribed to a single point mutation in the 3'-flanking region. We then found a novel point mutation in the coding region of the gene which results in the substitution of Ile for Val at residue 462 in the heme binding region. We further analyzed the genetic association between this amino acid replacement and MspI polymorphisms in the general population, using a new method to detect polymorphisms not recognized by restriction enzymes. The results showed that there are at least two forms of human P450IA1 protein with different primary structures and that one of the forms is closely linked with the lung cancer-susceptible genotype of MspI polymorphisms. Thus MspI polymorphisms, which are associated with increased risk of lung cancer, are linked to at least one amino acid substitution, which gives an important clue, at the molecular level, toward elucidation of increased susceptibility to lung cancer.

Amino Acid Sequence↗
PubMed1991

Clustering of liver cancer deaths in Saitama Prefecture, Japan.

Cancer statistics in 1965 revealed that people in the eastern part of Saitama had a high risk of developing cancer of the liver. Clusters of liver cancer were also observed in 1975, though less for males than for females. In 1985, traces remained of clusters with higher death rates from liver cancer. A field survey revealed absence of correlation between geographical clustering of liver cancer and HBsAg positivity, geographical HBsAg positivity differences between sexes, and lack of correlation between geographical distribution of HBsAg positivity and death rates from liver diseases (cancer or cirrhosis). There was no geographical relationship of death rates from liver cancer to liver cirrhosis in Saitama. Statistics of the Saitama Cancer Center revealed lower averages than in the rest of Japan for the percentage of HBsAg positivity in HCC inpatients, the percentage of HCC inpatients with liver cirrhosis, and the ratio between the number of patients with HCC and those with cholangio carcinoma. A mail questionnaire revealed that farmers in the eastern part of Saitama had a strong positive association with death from liver cancer. These results suggest that HBV does not play an important role in the clustering of high death rates from liver cancer in Saitama.

Adenoma, Bile Duct↗
PubMed1990

Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene.

A good correlation was observed between enhanced lung cancer risk and restriction fragment length polymorphisms (RFLPs) of the P450IA1 gene with the restriction enzyme MspI. Genotype frequencies of 0.49 for the predominant homozygote, 0.40 for the heterozygote, and 0.11 for the homozygous rare allele were observed in a healthy population. Among lung cancer patients, the frequency of homozygous rare allele of P450IA1 gene was found to be about 3-fold higher than that among healthy population, and this difference was statistically significant. This is the first report to identify the genetically high risk individuals to lung cancer at the gene level.

Adult↗
PubMed1990

Current urinary mass screening for catecholamine metabolites at 6 months of age may be detecting only a small portion of high-risk neuroblastomas: a chromosome and N-myc amplification study.

We studied 96 infants and children with untreated neuroblastomas. Chromosomes of tumor cells were analyzed in 68, and N-myc copy numbers were determined in 67 patients. Patients found by a mass screening program for 6-month-old infants (group A1, 39 patients) or those less than 12 months of age found clinically (group A2, 13 patients) were rarely in the disseminated stage (A1, three of 39; A2 one of 13); their tumors usually had near-triploid (3n) or hypertetraploid (greater than 4n) karyotypes (A1, 28 of 37; A2, nine of 11), and never had N-myc amplification (A1, zero of 34; A2, zero of 11). In contrast, children 12 months or over (group B, 27 patients) were usually in the disseminated stage (19 of 27) (P less than .0001); their tumors usually had near-diploid (2n) or near-tetraploid (4n) karyotypes (16 of 20) (P = .0027), and often had N-myc amplification (nine of 22) (P less than .0001). Of the 40 clinically found patients (A2 and B), six had undergone the screening with a negative result at the age of 6 months. Two of the six patients had N-myc amplification in the tumors. Most tumors found by the screening showed known characteristics predicting a good prognosis, and the majority of tumors showing characteristics predicting a poor prognosis were found in patients aged between 12 and 36 months. Our chromosome and N-myc amplification studies suggest that a low-risk tumor does not usually evolve to a high-risk tumor. Thus, the current mass screening program may be detecting only a small portion of highly malignant neuroblastomas at the earliest stage. Infants should be screened twice, at 6 months as well as at 12 months of age, for the early detection of high-risk neuroblastomas.

Age Factors↗