To investigate the CYP1A2 genotype-phenotype relationship and to compare CYP1A2 genetic polymorphisms and enzyme activity in terms of the effect of smoking and oral contraceptive (OC) use in Swedes ...and Koreans.
CYP1A2 enzyme activity was determined in 194 and 150 healthy Swedish and Korean subjects, respectively, on the basis of the 4-h plasma paraxanthine/caffeine (17X/137X) ratio determined using high-performance liquid chromatography. Genotyping for the -3860G>A, -2467delT, -739 T>G, -729 C>T, -163C>A and -3113A>G polymorphisms was performed by PCR-restriction fragment length polymorphism analysis.
The mean 17X/137X ratio was 1.54-fold higher in Swedes than in Koreans (mean difference: 0.16; 95% CI of the mean difference: 0.12, 0.20; p < 0.0001). Smokers had a significantly higher 17X/137X ratio (higher CYP1A2 activity) than non-smokers, while Swedish OC users had a significantly lower 17X/137X ratio than non-users (mean difference: 0.31, 95% CI of the mean difference: 0.23, 0.39; p < 0.0001). No effect of gender differences on enzyme activity was observed. Four known (CYP1A2*1A, *1D, *1F, and *1L) and two novel haplotypes (CYP1A2*1V and CYP1A2*1W) were found. CYP1A2*1K was rare in Swedes and absent in Koreans. No significant genotype-phenotype relationship was observed, with the exception of CYP1A2*1F in Swedish smokers, where it was associated with higher enzyme inducibility (p = 0.02). Koreans displayed a significantly lower mean 17X/137X ratio than Swedes having the same CYP1A2 genotype, smoking habit and OC use.
We found significant differences in CYP1A2 enzyme activity between Swedes and Koreans that could not be explained by environmental factors or the CYP1A2 haplotypes examined, despite differences in allele frequencies. None of the investigated CYP1A2 haplotypes are critical in inducing variations in enzyme activity, with the exception of CYP1A2*1F.
The aim of the present study was to evaluate the effects on the susceptibility to colorectal cancer (CRC) of genetic polymorphisms in P‐glycoprotein (PGP) and the metabolic enzymes cytochrome P450 ...1A2 (CYP1A2) and flavin‐containing monooxygenase 3 (FMO3). We analyzed five single‐nucleotide polymorphisms (SNP) in 93 cancer‐free volunteers and 111 patients with CRC: one common genetic variant of the PGP‐encoding MDR1 gene and four SNP in genes for metabolic enzymes (two SNP in FMO3 and two SNP in CYP1A2). The genotypes and allele frequencies of the MDR1/C3435T, FMO3/G488A, FMO3/A923G and CYP1A2/G‐3860 A polymorphisms were not significantly different in cancer‐free subjects and CRC patients. However, a significant association was found between the CYP1A2/A‐163C polymorphism and the risk of CRC, particularly in elderly (>55 years) subjects and smokers. A phenotyping study in normal smokers showed that the CYP1A2 activity of subjects with the CYP1A2/−163 AA genotype was significantly lower than that of subjects carrying the CYP1A2/−163C allele. Combined results show that the CYP1A2/−163C allele is significantly associated with an increase in CYP1A2 activity and a consequent increased risk of CRC in Koreans, particularly in elderly people and smokers. (Cancer Sci 2006; 97: 774–779)
Context: The reproductive endocrinology in Asians and Caucasians is of great interest in view of large differences in prostate cancer rate and sensitivity to pharmacological male contraception. In ...addition, interpretation of certain antidoping tests is confounded by interethnic variation in androgen disposition. Uridine diphosphoglucuronosyl transferases have a key role in the homeostasis and metabolism of androgens. Recently a deletion polymorphism was detected in the UGT2B17 gene.
Objective: The objective of the study was to evaluate the contribution of the UGT2B17 deletion polymorphism to the interindividual and interethnic variation of androgen metabolism and excretion.
Methods and Results: Urine from 122 Swedish and 74 Korean healthy men was analyzed for several androgen glucuronides including testosterone. The distribution of the natural logarithms of urinary testosterone concentrations showed a distinct bimodal pattern in both groups, suggesting a monogenic inheritance. When the UGT2B17 genotypes were compared with urinary testosterone levels, all of the individuals of the UGT2B17 homozygous deletion/deletion genotype had no or negligible amounts of urinary testosterone. The deletion/deletion genotype was seven times more common in the Korean (66.7%) than the Swedish population (9.3%). In addition, the Swedes had significantly higher levels of serum testosterone, compared with the Koreans.
Conclusions: Our results show that the UGT2B17 polymorphism is strongly associated with the bimodal distribution of the testosterone excretion and also with the large differences in testosterone excretion between Koreans and Swedes.
The aim of this study was to compare xanthine oxidase (XO) and N-acetyltransferase-2 (NAT2) genotype and phenotype between Swedes (n = 113) and Koreans (n = 150), as well as to investigate the effect ...of sex, smoking, age, and oral contraceptive (OC) use on enzyme activities, using caffeine as a probe. XO and NAT2 activities were estimated by 1U/(1U+1X) and AFMU/(AFMU+1X+1U) urinary ratios, respectively. Participants were genotyped for 191G>A, 341T>C, 590G>A, and 857G>A NAT2 polymorphisms. There was no significant difference in XO activity between Swedes and Koreans. In Swedes, higher XO activity was observed in women (P < .003). There were significant differences in NAT2 genotype and phenotype between Swedes and Koreans. Koreans display significantly higher frequency of NAT2 fast acetylator genotype (89%), whereas the slow acetylator genotype is predominant (62%) in Swedes (P < .0001). Significantly higher NAT2 activity was observed in Koreans compared to Swedes (P < .0001). Having the same NAT2 fast acetylator genotype, Koreans display higher enzyme activity than Swedes (P < .004). OC use significantly increased NAT2 activity in Swedish women. In conclusion, Koreans display higher NAT2 activity than Swedes regardless of NAT2 genotype. Ethnicity, OC use, and genotype determine NAT2 activity, whereas sex is the only determinant of XO activity.
Objectives To compare CYP2C19 enzyme activity between Swedes and Koreans controlling for the effect of CYP2C19 genotype, sex, oral contraceptive use, and smoking habits. Methods CYP2C19 activity was ...determined in 185 healthy Swedish and 150 Korean subjects as the omeprazole/5-hydroxyomeprazole ratio (metabolic ratio; MR) using high-performance liquid chromatography. Genotyping was performed by PCR using Taqman assay. Results As expected, a higher incidence of poor metabolizers (PM) was found in Koreans (14%) compared with Swedes (3.8%) and the frequency of the CYP2C19*17 allele was very low in Koreans (0.3%). Among subjects homozygous for CYP2C19*1, Koreans displayed significantly lower CYP2C19 enzyme activity than Swedes (p < 0.000001). Interestingly, in Koreans a pronounced gender difference was apparent: females (n = 24) had significantly lower MR than males (n = 30; p < 0.0001), but such a gender difference was not seen among Swedes. Swedish OC users had a higher MR than non-users (p < 0.00001), whereas OC was only used by one Korean. No effects of smoking were observed. Conclusions We find specific gender-dependent effects of CYP2C19 activity in Koreans, but not in Swedes. Controlling for the effect of genotype and sex, Koreans display lower CYP2C19 activity than Swedes. The genetic, epigenetic or environmental basis for this difference remains to be identified.
The aim was to compare cytochrome P450 2A6 (CYP2A6) genotype and enzyme activity between Swedes and Koreans, and to investigate the influence of genotype, sex, age, cigarette smoking and oral ...contraceptive (OC) use on enzyme activity. The study involved 190 Swedes and 144 Koreans. Genotyping for CYP2A6*1B, *1 × 2, *4, *5, *7, *8, *9, *10, *18 and *19 alleles was done. Using caffeine as a probe, in vivo CYP2A6 activity was estimated by the 17U/17X urinary ratio. Multiple regression analysis indicated ethnicity (p = 0.0001) and CYP2A6 genotype (p = 0.006), but not sex, age, cigarette smoking or OC use as predictors of CYP2A6 activity. There were significant differences in CYP2A6 genotype distribution and enzyme activity between Swedes and Koreans. Functional CYP2A6 alleles and rapid genotypes were more frequent in Swedes, whereas the defective alleles and slow genotypes were more frequent in Koreans (p ≤ 0.0001). Distribution of log 17U/17X was bimodal in Koreans but unimodal in Swedes with a common antimode at 0.01, classifying 3.16% of Swedes and 18.75% of Koreans as slow metabolizers. CYP2A6 activity was higher in Swedes compared to Koreans (p < 0.0001), even among carriers of rapid genotypes. We report major differences in CYP2A6 enzyme activity between Swedes and Koreans mainly due to CYP2A6 genetic variation but not exclusively.
OBJECTIVESTo study the potential endogenous marker of CYP3A activity, 4β-hydroxycholesterol, and its relation to sex and the CYP3A5 geno/haplotypes and compare with CYP3A4/5 catalyzed 3-hydroxylation ...of quinine in the three major races.
METHODSThe plasma concentration of 4β-hydroxycholesterol was measured in healthy Tanzanians (n=138), Swedes (n=161) and Koreans (n=149) by gas chromatography–mass spectrometry. The metabolic ratio of quinine/3-hydroxyquinine in plasma 16-h post dose was determined by high performance liquid chromatography, previously reported in Tanzanians and Swedes, and now also in Koreans. The participants were genotyped for relevant alleles of CYP3A5.
RESULTSThe mean plasma concentrations of 4β-hydroxycholesterol in Koreans, Swedes and Tanzanians were 29.3, 26.8 and 21.9 ng/ml, respectively (P<0.01 between all three populations). Within all three populations there were significant differences in 4β-hydroxycholesterol levels between the CYP3A5 genotypes. Women had higher concentrations than men, but the difference was only significant in Tanzanians (P<0.001) and Koreans (P<0.00001). The quinine/3-hydroxyquinine metabolic ratio was significantly different in all three populations with the highest CYP3A activity in Koreans and the lowest in Tanzanians. Korean women had a lower metabolic ratio than men (P<0.00001). Significant correlations between 4β-hydroxycholesterol and quinine 3-hydroxylation were found in Tanzanians and Koreans.
CONCLUSIONClear differences in the activity of both CYP3A4 and CYP3A5 were shown in the three major human races. Both 4β-hydroxycholesterol and quinine/3-hydroxyquinine metabolic ratio showed a higher CYP3A activity in women than in men. The results give strong evidence that the plasma concentration of 4β-hydroxycholesterol may be used as an endogenous marker of CYP3A activity (CYP3A4+5).
In vitro studies have shown that vitamin D may induce several cytochrome P450 (CYP) enzymes in general and CYP3A4 in particular. The primary aim of this study was to investigate the relationship ...between plasma levels of 25‐hydroxyvitamin D3 and suggested in vivo markers of CYP3A activity in healthy volunteers from Sweden and Korea. Plasma concentrations of 25‐hydroxyvitamin D3 were analysed in samples from three previously performed studies, and the correlation between these levels and suggested in vivo markers of CYP3A activity was investigated by means of nonparametric correlation. In addition, we studied the modulating effects of three vitamin D receptor promoter polymorphisms on the association between 25‐hydroxyvitamin D3 and CYP3A enzyme activity in Swedish subjects. The plasma levels of 25‐hydroxyvitamin D3 were not significantly associated with CYP3A phenotypes in any of the three studies, but after accounting for the vitamin D receptor polymorphism rs4516035, there was a significant positive association between 25‐hydroxyvitamin D3 and CYP3A activity (p = 0.004). Swedes (n = 65) had significantly higher 25‐hydroxyvitamin D3 levels than Koreans (n = 67), 75 nM compared with 31 nM (p < 0.001). Swedish women taking oral contraceptives (OC) (n = 19) had somewhat higher plasma levels of 25‐hydroxyvitamin D3 compared with Swedish women not taking oral contraceptives (n = 21), 89 and 72 nM, respectively (p = 0.02). In conclusion, our results suggest that the overall influence on the CYP3A activity by 25‐hydroxyvitamin D3 is of marginal importance.
Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is ...subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p<0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.
PDF
