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PubMed2005

Genetic polymorphisms in glutathione-S-transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma.

BACKGROUND: It has been suggested that genetic polymorphisms in certain glutathione-S-transferase (GST) genes reduce the effectiveness of detoxifying cytotoxins generated by chemotherapeutic agents, potentially resulting in enhanced clinical responses to chemotherapy. METHODS: The authors evaluated common polymorphisms in the GSTM1, GSTT1, and GSTP1 genes for associations with overall survival in 1034 patients with invasive breast carcinoma who were recruited into the Shanghai Breast Cancer Study between 1996 and 1998, treated with chemotherapy, and followed for a median of 5.3 years. RESULTS: After adjusting for age, tumor stage, and the use of radiotherapy and tamoxifen, women who were homozygous for the variant GSTP1 105Val allele had a 60% reduction in mortality risk compared with women who were homozygous for the Ile allele (hazard ratio, 0.4; 95% confidence interval, 0.2-0.8). No association was found with respect to any of the GSTM1 or GSTT1 genotypes. CONCLUSIONS: The results of the current study indicate a potential role for GSTP1 polymorphism in predicting the clinical outcomes of patients with breast carcinoma who are treated with chemotherapy.

Acyltransferases↗
PubMed2002

An approach for the quantitative consideration of genetic polymorphism data in chemical risk assessment: examples with warfarin and parathion.

In recent years, a great deal of research has been conducted to identify genetic polymorphisms. One focus has been to characterize variability in metabolic enzyme systems that could impact internal doses of pharmaceuticals or environmental pollutants. Methods are needed for using this metabolic information to estimate the resulting variability in tissue doses associated with chemical exposure. We demonstrate here the use of physiologically based pharmacokinetic (PBPK) modeling in combination with Monte Carlo analysis to incorporate information on polymorphisms into the analysis of toxicokinetic variability. Warfarin and parathion were used as case studies to demonstrate this approach. Our results suggest that polymorphisms in the PON1 gene, that give rise to allelic variants of paraoxonase, which is involved in the metabolism of paraoxon (a metabolite of parathion), make only a minor contribution to the overall variability in paraoxon tissue dose, while polymorphisms in the CYP2C9 gene, which gives rise to allelic variants of the major metabolic enzyme for warfarin, account for a significant portion of the overall variability in (S)-warfarin tissue dose. These analyses were used to estimate chemical-specific adjustment factors (CSAFs) for the human variability in toxicokinetics for both parathion and warfarin. Implications of alternatives in the calculation of CSAFs are explored. Key decision points for applying the PBPK-Monte Carlo approach to evaluate toxicokinetic variability for other chemicals are also discussed.

Animals↗
PubMed2000

Effect of a genetic polymorphism of CYP1A2 inducibility on the steady state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia.

The effect of a genetic polymorphism of inducibility of cytochrome P450 (CYP) 1A2 on the steady state plasma concentrations (Css) of haloperidol and reduced haloperidol was studied to clarify if these Css are dependent on the CYP1A2 activity. The subjects were 101 Japanese schizophrenic inpatients receiving oral haloperidol 12 mg/d. The Css of haloperidol and reduced haloperidol were measured in duplicate by high performance liquid chromatographic method, and were corrected to the mean body weight. A point mutation from guanine (wild-type) to adenine (mutated-type) at position -2964 in the 5'-flanking region of CYP1A2 gene was identified by polymerase chain reaction (PCR)-fragment length polymorphism method. Based on the present results, i.e., significant effects of CYP2D6 genotypes on the Css of haloperidol and reduced haloperidol, analyses were separately performed in two groups, i.e., patients with 0 mutated allele of the CYP2D6 (41 cases) and those with 1 or 2 mutated alleles (60 cases). Subjects in each CYP2D6 genotype group consisted of 4 subgroups according to smoking habit and the presence of the mutated allele of the CYP1A2. Neither the Css of haloperidol nor that of reduced haloperidol significantly differed among the 4 subgroups in either CYP2D6 genotype group. The present study thus suggests that the CYP1A2 activity does not play an important role in controlling the Css of haloperidol or reduced haloperidol.

Alleles↗
PubMed1995

Genetic polymorphism of the sixth component of complement (C6) in dogs.

Using agarose gel isoelectric focusing and immunoblotting with rabbit anti-rabbit C6, a genetic polymorphism was found in the sixth component of complement (C6) in 18 Asian native breeds or populations and three European breeds of dog. The C6 locus was highly polymorphic. The phenotype distribution data indicated that dog C6 phenotypes were controlled by seven codominant alleles, C6A,C6B,C6C,C6D,C6E,C6F and C6G, at a single autosomal locus. Breed differences were observed among the gene frequencies, especially between Asian and European breeds. Two gene flows from the adjacent areas into Japanese native dogs were postulated.

Animals↗
PubMed2004

[Genetic polymorphisms of 6 Y-chromosome specific STR loci in the southern Chinese Han population and its application in forensic science].

To study the genetic polymorphisms of six Y-chromosome specific STR loci in the southern Chinese Han population and apply it in forensic science, six Y-STR loci were amplified by multiple PCR and the PCR products were detected by using ABI Prism 377 Sequencer. The haplotype frequencies at 6 Y-STR loci were determined in a total of 204 unrelated males from southern Han population of China. Ninety-three father/son pairs with demonstrated paternity and thirty-eight non-paternity father/son pairs were detected by using our Y-STR system. As a result, the number of alleles for DYS393, DYS19, DYS389 II, DYS390, DYS391 and DYS385 were 5, 6, 8, 6, 4 and 44, respectively. A total of 176 haplotypes at 6 Y-STR loci were found. Two father/son pairs with single Y-STR mutation were observed in the 93 father/son pairs with demonstrated paternity. Among the 38 non-paternity father/son pairs, one case with one Y-STR exclusion of paternity, one case with two Y-STR exclusions and 35 cases with 3 or more Y-STR exclusions were observed. Non-exclusion of paternity at 6 Y-STR loci was found only in one case. This result indicated that the six Y-STR loci were highly polymorphic and are suitable for personal identification and paternity testing.

Asian People↗
PubMed2006

The missense genetic polymorphisms of human CYP2A13: functional significance in carcinogen activation and identification of a null allelic variant.

Cytochrome P450 2A13 (CYP2A13), an enzyme predominantly expressed in human respiratory tissues, is highly efficient for the metabolic activation of two suspected human lung carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and aflatoxin B1 (AFB1). Functional genetic polymorphisms of CYP2A13 may therefore be an important factor in human susceptibility to related lung cancers. Among the reported CYP2A13 polymorphisms with missense variations, only CYP2A13*2 variant (containing either a single or double variation of R25Q and R257C) was studied for its NNK-metabolizing activity. The present study demonstrated that there was no remarkable difference in AFB1- and NNK-induced toxicity between the Flp-In Chinese Hamster Ovary (CHO) cells stably expressing wild-type CYP2A13 and the cells expressing the individual polymorphic variants R25Q, D158E, R257C, R25Q/R257C, V323L, F453Y, and R494C. In contrast, cells transfected with R101Q variant complementary DNA (cDNA), same as the vector control cells, showed no significant death even at highest concentrations of AFB1 (10microM) and NNK (200microM). This result correlated with the lack of CYP2A13 protein in the R101Q-CHO cells, although the genomic integration of transfected R101Q cDNA and the expression of R101Q messenger RNA were clearly demonstrated in these stable transfectants. Consistent with the possibility that the variation might reduce the protein stability, R101Q variant protein expressed in insect cells showed a loss of P450 peak and coumarin 7-hydroxylase activity as well as an increased susceptibility to limited protein digestion. Thus, the R101Q polymorphic change results in a null allelic variant of CYP2A13. Our results should be useful in designing and interpreting molecular epidemiological studies related to CYP2A13 genetic polymorphisms.

Aflatoxin B1↗
PubMed2005

Folate, vitamin B6, vitamin B12, and vitamin B2 intake, genetic polymorphisms of related enzymes, and risk of colorectal cancer in a hospital-based case-control study in Japan.

We conducted a case-control study to investigate the association of nutrient intake involved in the one-carbon pathway of folate for DNA methylation and DNA synthesis and the related enzyme genetic polymorphisms with colorectal cancer. Cases were 107 patients newly diagnosed with colorectal cancer. Controls were 224 subjects matched with cases by sex, age, and residential area. Nutrient intake was assessed by a self-administered, semiquantitative food-frequency questionnaire. Four genetic polymorphisms-MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys-were determined using blood samples. Odds ratios were calculated using conditional logistic regression analysis adjusted for smoking, alcohol consumption, body mass index, and dietary fiber intake. Although folate intake was inversely associated with colorectal cancer, this association was attenuated after further controlling for dietary fiber intake. Neither vitamin B6, vitamin B12, nor vitamin B2, nor any genetic polymorphism was significantly associated with colorectal cancer. MTRR polymorphism interacted with the association of folate (P for interaction = 0.04) or vitamin (P for interaction = 0.02) with colorectal cancer, although the other polymorphisms did not interact with any nutrient intake. In conclusion, the study did not support the existing hypothesis of gene-nutrient interaction in colorectal carcinogenesis.

Adult↗
PubMed2005

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism.

Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "soft-nucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics. In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences. The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

Amino Acid Sequence↗
PubMed2004

The role of genetic polymorphisms in metabolism of carcinogenic heterocyclic aromatic amines.

More than twenty heterocyclic aromatic amines (HAAs) have been identified in grilled meats, fish, poultry, and tobacco smoke condensate. HAAs are carcinogens and induce tumors at multiple sites in experimental laboratory animals. Because of the widespread occurrence of HAAs in foods, these chemicals may contribute to the etiology of several common human cancers that are associated with frequent consumption of grilled meats including colon, rectum, prostate, and breast. HAAs require metabolism in order to exert their genotoxic effects. Metabolic activation occurs by N-hydroxylation, a reaction catalyzed by cytochromes p450 (CYP). Some N-hydroxy-HAA metabolites may directly react with DNA, but further metabolism by N-acetyltransferases (NATs) or sulfotransferases (SULTs) may occur to form highly reactive N-acetoxy or N-sulfonyloxy esters that readily react with DNA bases. The N-acetoxy ester of the HAA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is detoxified by glutathione S-transferases (GSTs), which catalyze the reduction of the reactive intermediate back to the parent amine. Some HAAs also undergo detoxification through conjugation reactions with the phase II enzymes such as UDP-glucuronosyltransferases (UGTs) or SULTs to form stable, polar products that are readily eliminated. All of these xenobiotic metabolism enzyme systems (XMEs) display common genetic polymorphisms, which may affect protein expression, protein stability, catalytic activity, and thus, the biological potency of these procarcinogens. In this review, the roles of common genetic polymorphisms of XMEs involved in HAA metabolism and cancer risk are discussed.

Amines↗
PubMed2005

Dose-dependent influence of genetic polymorphisms on DNA damage induced by styrene oxide, ethylene oxide and gamma-radiation.

Styrene oxide (SO), ethylene oxide (EO) and gamma-radiation (G) are agents with a well-described metabolism and genotoxicity. EPHX1 and GSTs play an important role in the detoxification of electrophiles and oxidative stress. Enzymes involved in base excision repair (hOGG1, XRCC1), in rejoining single strand breaks (XRCC1) and in repair of cross-links and chromosomal double strand breaks (XRCC3) might have an impact on genotoxicity as well. In this study we assessed the dose-dependent effect of genetic polymorphisms in biotransforming (EPHX (Tyr113/His113 and His139/Arg139), GSTP1 (Ile105/Val105), GSTM1 and GSTT1) and DNA repair enzymes (hOGG1 (Ser326/Cys326), XRCC1 (Arg194/Trp194, Arg280/His280, Arg399/Gln399), XRCC3 (Thr241/Met241)) on the induced genotoxicity. Peripheral blood mononuclear cells from 20 individuals were exposed to 3 doses per agent (+control). Genotoxicity was evaluated by measuring comet tail length (TL) and micronucleus frequencies in binucleated cells (MNCB). Dose-dependent DNA damage was found for all agents and end-points, with the exception of MNCB induced by EO. Repeated measure ANOVA revealed a significant contribution of hOGG1 and XRCC3 genotypes to the inter-individual variability of TL and MNCB in cells exposed to EO and G. Homozygous hOGG1326 wild cells showed significantly lower EO-induced TL than the heterozygous cells. Significantly higher TL and MNCB were found in EO-exposed cells carrying the XRCC3(241)Met variant and the influence on TL was more pronounced at higher dose. In G-irradiated cells, TL was significantly higher in the hOGG1326 homozygous wild types compared with mutated genotypes. The influence of hOGG1326 on TL was borderline dose-dependent. We conclude that the influence of genetic polymorphisms of enzymes involved in DNA repair on induced genotoxicity depends on exposure dose.

Adult↗
PubMed1997

Genetic polymorphism of CYP2C19 and lansoprazole pharmacokinetics in Japanese subjects.

OBJECTIVE: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the genetic polymorphism of CYP2C19 which occurred by two mutations. CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects. METHODS: Polymerase chain reaction (PCR) restriction fragment length polymorphism procedures were used to detect the CYP2C19m1 mutation in exon 5 and the CYP2C19m2 mutation in exon 4 using SmaI and BamHI, respectively. RESULTS: Ten subjects were homozygous (wt/wt subjects) for the wt allele in both exon 5 and exon 4, four subjects were heterozygous (wt/m1) for the CYP2C19m1 mutation, and two subjects were heterozygous (wt/m2) for the CYP2C19m2. The remaining four subjects had both mutated alleles in CYP2C19 genes, i.e., two were homozygous (m1/m1) for the defect in exon 5 and two were heterozygous (m1/m2) for the two defects in exons 5 and 4. The subjects in group 1 (wt/wt, wt/m1 and wt/m2) were the extensive metabolizers (EMs) for 5-hydroxylation of lansoprazole and were in the range of hydroxylation indexes from 3.83 to 19.8, whereas the subjects in group 2 (m1/m1 and m1/m2) were the poor metabolizers (PMs) and the indexes were in the range of 38.5 to 47.6. In group 2, AUC, t1/2 and CL/f of lansoprazole were significantly greater, longer, and lower, respectively, than those in group 1.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1997

Interaction between obesity and genetic polymorphisms in the apolipoprotein CIII gene and lipoprotein lipase gene on the risk of hypertriglyceridemia in Chinese.

To understand the effects of the interaction between genetic polymorphisms and obesity on the risk of hypertriglyceridemia (HTG), two polymorphisms, an SstI polymorphism on the apolipoprotein CIII gene and a HindIII polymorphism on the lipoprotein lipase gene, were analyzed in 339 Chinese subjects with (82 cases in the HTG group) or without HTG (257 cases in the control group). Our data revealed that the frequencies of obesity, the SstI minor allele (S2), and the HindIII major allele (H+) in the HTG group were significantly higher than in the control group. Subgroup analysis revealed that the association between these two polymorphisms and HTG occurred predominantly in nonobese subjects and in subjects with the less hypertriglyceridemic genotype of another polymorphism. Multivariate logistic regression analysis showed that all three risk factors (obesity, S2-containing chromosome, and H+ homozygosity) were associated with HTG, and an interaction was found between obesity and H+ homozygosity for the occurrence of HTG. The risk of HTG increased significantly with combinations of risk factors. Subjects can be divided into low or high risk groups for HTG using such combinations. These results provide evidence of interaction between obesity and the HindIII polymorphism of the lipoprotein lipase gene on the risk of HTG.

Alleles↗
PubMed2001

[Renin-angiotensin system genetic polymorphisms and essential hypertension in the Spanish population].

BACKGROUND: The goal of this study was to analyse the association between essential hypertension and the main genetic polymorphisms at the renin-angiotensin system in the Spanish population. PATIENTS AND METHOD: Case-control study including 185 essential hypertensive subjects(age [SD] 39.6 [7.5] years, 52% women, systolic blood pressure 151.2 [17.4] mmHg, diastolic blood pressure 96.0 [9.4] mmHg) and 350 sex- and age-matched normotensive individuals selected from a sample of the general population of the Comunidad Valenciana, Spain (age 39.4 [8.0] years, 51.7% women, systolic blood pressure 116.0 [12.0] mmHg, diastolic blood pressure 69.6 [8.5] mmHg). A PCR was performed to determine I/D angiotensin converting enzyme (ACE) gene polymorphism, A-6G and M235T angiotensinogen gene polymorphism and A1166C polymorphism of the angiotensin II type 1 receptor. RESULTS: There were no differences between cases and controls with regard to genotypic and allelic distributions. In hypertensive patients,there were no differences in genotypic or allelic distributions after considering the presence or absence of a familial history of hypertension or comparing tertiles of systolic and diastolic blood pressure values. Only in women, the combination of a C allele of A1166C polymorphism with an A-6G angiotensinogen polymorphism A allele (p = 0.007), or an M235T angiotensinogen polymorphism T allele (p = 0.007), was associated with a higher risk of hypertension. CONCLUSIONS: We found no association between essential hypertension risk and I/D ACE gene, M235T and A-6G angiotensinogen gene, or A1166C angiotensin II type 1 receptor gene polymorphisms. An epistatic effect was observed in young women between angiotensin II type 1 receptor polymorphisms and angiotensinogen polymorphisms.

Adolescent↗
PubMed1998

Analysis of genetic polymorphisms related to thrombosis and other risk factors in patients with retinal vein occlusion.

The purpose of this study was to investigate the role of genetic polymorphisms associated with venous and arterial thrombosis in patients with retinal vein occlusion (RVO). One-hundred and two consecutive patients with RVO were examined for factor V G1691A and factor II G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and apolipoprotein E4 by amplification of specific DNA fragments and restriction analysis. The risks exerted by these polymorphisms and by the conventional risk factors of RVO were evaluated by comparing their frequencies among patients and controls and by estimating the respective odds ratios. We found that the prevalences of the factor V G1691A, factor II G20210A, and apolipoprotein E4 polymorphisms were similar in the study and control groups. Logistic regression analysis involving the parameters for which significant differences were detected disclosed an odds ratio of 1.9 for MTHFR C677T homozygosity (95% confidence interval 0.95-3.81), an odds ratio of 2.12 for hypertension (95% confidence interval 1.16-3.73) and an odds ratio of 3.25 for a family history of stroke (95% confidence interval 1.07-9.51). Our data suggests that homozygosity for the MTHFR C677T polymorphism is a risk factor of RVO in addition to arterial hypertension and a family history of stroke.

Adult↗
PubMed1993

Genetic polymorphism of the sixth component of complement (C6) in the pig.

Using agarose gel isoelectric focusing and immunoblotting with rabbit anti-rabbit C6, a genetic polymorphism has been found in the sixth component of complement (C6) in six breeds of pigs. The C6 locus was highly polymorphic. Family data indicated that pig C6 phenotypes were inherited by means of five codomonant alleles named C6A, C6B, C6C, C6D and C6E at a single autosomal locus. C6 deficiency in two of 241 individuals tested was found, which suggested the presence of a null allele in pig populations. Marked breed differences among the gene frequencies and heterozygosities at C6 locus were observed.

Animals↗
PubMed2006

Total homocysteine, folate, and cobalamin, and their relation to genetic polymorphisms, lifestyle and body mass index in healthy children and adolescents.

We investigated total homocysteine (tHcy) concentrations and relations between tHcy and folate, cobalamin (Cbl), genetic polymorphisms (MTHFR 677C > T, MTHFR 1298A > C, MTHFR 1793G > A), blood pressure (BP), body mass index (BMI), cholesterol, triglycerides, sports activities, family and individual history of cardiovascular disease (CVD) and lifestyle issues in 264 healthy children and adolescents (2-17 y). THcy concentrations significantly increased while folate and Cbl decreased with age without gender differences. Age, folate and Cbl were significant predictors for tHcy concentrations. THcy was higher but within normal ranges in MTHFR 677TT homozygotes (10.6%) and carriers of the MTHFR 1793A allele (8%). Only two individuals (0.8%), both with low tHcy concentrations, were homozygous for MTHFR 1793AA. THcy concentration correlated positively with creatinine, triglycerides, BMI and systolic BP and was not related to cholesterol, sports activities and family history of CVD. In conclusion, tHcy concentrations in this pediatric population were significantly influenced by age, folate and Cbl concentrations. No gender differences for tHcy, folate or Cbl concentrations were observed. Both the MTHFR 677TT genotype and the MTHFR 1793A allele were not associated with hyperhomocysteinemia. The prevalence of the MTHFR 1793AA genotype was too low for meaningful interpretation.

Adolescent↗
PubMed1998

[Genetic polymorphisms of FABP2 and F13A1 loci in Han population].

OBJECTIVE: To find more STR loci usable in forensic medicine and understand the distribution of the genetic polymorphisms of two STR loci FABP2 and F13A1 in the Han population in Chengdu. METHODS: EDTA-blood specimens were collected from 115 healthy unrelated Han individuals in Chengdu, DNA was extracted using Chelex method. The DNA samples were amplified by PCR technique, and the PAGE horizontal electrophoresis was used for typing of the PCR products. RESULTS: The allele frequencies were FABP2*1:0.513,FABP2*2:0.096, FABP2*3:0.330, FABP2*4:0.052, FABP2*5:0.009, and 10 genotypes were observed in 115 individuals for FABP2; while for F13A1, the allele frequencies were F13A1*1:0.128, F13A1*2: 0.053, F13A1*3:0.288, F13A1*4:0.527, F13A1*5:0.004 and 10 genotypes were observed in 113 individuals. The result of test for Hardy-Weinberg equilibrium showed that the genotype distribution observed at FABP2 locus was correspondent with the expected. CONCLUSION: FABP2 may be a useful marker for paternity test or personal indentification of biological stain. On the other hand, more studies need to be done to understand the polymorphism at F13A1 locus in Chinese population because a deviation from Hardy-Weinberg equilibrium has been observed in this Han population.

Carrier Proteins↗