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1.
Genetic variations in cytochrome P450 2C9 are known to contribute to interindividual and interethnic variability in response to clinical drugs, but little is known about the genetic variation of CYP2C9 in the Uyghur population. We directly sequenced the whole CYP2C9 gene in 96 unrelated, healthy Uyghur from Xinjiang Uygur Autonomous Region of China and screened for genetic variants in the promoter, exons, introns and 3′-UTR. Thirty five previously reported alleles and six genotypes were detected in this study. The allele frequencies of CYP2C9*1, *2, *11, *12, *29 and *33 were 89.58, 7.81, 0.52, 0.52, 1.04 and 0.52%, respectively. We detected one non-synonymous novel variant at position 329 from Arg to Cys and this mutation is predicted to be intolerant by SIFT. Our results provide basic information about CYP2C9 alleles in Uyghur, which may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group. 相似文献
2.
1.? CYP2C19 is a clinically important enzyme and is involved in the metabolism of approximately 10% of drugs used in daily clinical practice. Previous studies mainly focused on Chinese Han populations or other ethnic groups, little is known about Uyghur populations.2.?The present study was designed to determine the genetic basis of CYP2C19 polymorphisms.3.?We used direct sequencing to investigate the promoter, exons and surrounding introns, and 3′-untranslated region of the CYP2C19 gene in 96 unrelated healthy Uyghur individuals.4.?A total of 31 different CYP2C19 polymorphisms were identified in the Uyghur population, three of which were novel, including two nonsynonymous variants (57807A?>?M, Gln279Pro and 19257G?>?R, Asp262Asn) and one synonymous variants in exon 5 (19184T?>?Y, Leu237Leu). In addition, CYP2C19*1, *2 and *3 alleles showed frequencies of 83.34%, 14.06% and 2.08%, respectively.5.?This is the first study that systematically screened the polymorphisms of the whole CYP2C19 gene in Uyghur population. Hence, our results provided important information on CYP2C19 polymorphisms in Uyghur population and could be helpful for future personalized medicine studies in Uyghur population generally. 相似文献
3.
1. Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy.2.?We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3′-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions.3.?We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C?>?T in exon 1, two mutations 32120C?>?G and 32245T?>?C in 3′-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype “TTAGGT” was the most prevalent with 0.781.4.?Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs. 相似文献
4.
AIMS: To evaluate the effect of the CYP1A2*1C and CYP1A2*1F polymorphisms on the inducibility of CYP1A2 by omeprazole in healthy subjects. METHODS: Mutations of CYP2C19 and CYP1A2 were identified by PCR-RFLP. Omeprazole, 120 mg day-1, was given to 12 extensive metabolizers (EM) with respect to CYP2C19 (six CYP1A2*1F/CYP1A2*1F and six CYP1A2*1C/CYP1A2*1F of CYP1A2) for 7 days. CYP1A2 activity was determined on three occasions, namely on day 1, day 9 and day 16 using the caffeine plasma index (the ratio of the concentrations of paraxanthine to caffeine), 6 h after oral administration of 200 mg caffeine. RESULTS: There was a significant difference (P = 0.002) between the caffeine ratios for CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes on day 9, but not on day 1 or day 16 (P > 0.05). The changes in the ratios from day 9 to day 1 (48% +/- 20%vs 19% +/- 20%) and from day 9 to day 16 (50% +/- 31%vs 15% +/- 22%) were significantly different (P < 0.05) between the CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes. CONCLUSION: The CYP1A2*1C and CYP1A2*1F genetic polymorphisms influenced the induction of CYP1A2 activity in vivo by omeprazole. 相似文献
5.
Since human cytochrome P450 2F1 (CYP2F1) is predominantly expressed in lung tissue and is involved in the metabolism of various pneumotoxicants with potential carcinogenic effects, variations in the nucleotidic sequence of its gene may contribute to interindividual and interethnic differences in the susceptibility to lung tumorigenesis. The aim of the current study was to compare the frequency of a previously reported frameshift mutation, namely c.14_15insC, responsible for the synthesis of a severely truncated protein, between several populations of different ethnic origins. The frequencies of this polymorphism were 26.1, 51.6, 42.7 and 22.9% in French, Gabonese, Senegalese, and Tunisian population samples, respectively, thereby representing a substantial inter ethnic variation in the CYP2F1 gene. These findings provide data for further studies that investigate the potential association of CYP2F1 haplotypes with an incidence of lung cancer genesis in respect of ethnicity. 相似文献
6.
CYP1A2 is a cytochrome P450 which is inducible by polycyclic aromatic hydrocarbons. This induction could be mediated via the Ah locus, which encodes a cytosolic receptor responsible for the regulation of the CYP1A1 gene. Enzyme activity in vivo can be measured by the urinary caffeine metabolite ratio (AFMU+1X+1U)/17U. Our goal was to determine, using this ratio, the possible existence of a genetic polymorphism in CYP1A2 induction. For this purpose, a population and family study, including smokers, were undertaken. In a first step, we investigated factors influencing enzyme activity in a population of 245 unrelated individuals.The induction effect of smoking and inhibiting effect of oral contraceptive use were confirmed. None of the other factors examined (age, sex, level of cigarette consumption, nicotine or tar amounts, filter, inhalation) accounted for the interindividual variability in the metabolic ratio. Using the statistical SKUMIX method, a unimodal (one peak) distribution of the ratio was concluded in 164 unrelated smokers, since a second distribution did not significantly improve the fit to the data ( x
21=1.39, P>0.2). Segregation analysis was performed on 68 nuclear families and no major gene effect could be shown. Furthermore, the polygenic model did not provide a higher likelihood than the sporadic one, which argues against the existence of any familial resemblance. Although we cannot rule out the possibility that some environmental factors could obscure the phenotypes and occult a genetic determinism, we conclude that genetic factors are probably negligible in the determination of CYP1A2 activity measured by this method.These results suggest that CYP1A2 induction via the Ah locus would not be similar to that of CYP1A1. 相似文献
7.
AIMS: To investigate the influence of the CYP1A2*1F mutation on CYP1A2 activity in smoking and nonsmoking pregnant women. METHODS: Pregnant women (n = 904) who served as control subjects in a case-control study of early fetal loss were investigated. They were phenotyped for CYP1A2 using dietary caffeine and the urinary ratio AFMU + 1X + 1 U/1,7 U. An assay for CYP1A2*1F using 5'-nuclease assay (Taqman) was developed to genotype the population. RESULTS: The frequencies of *1 A and *1F alleles among Swedish women were 0.29 and 0.71, respectively. There was no statistically significant difference in CYP1A2 activity between the genotypes, although a trend towards enhanced activity was observed in *1F/*1F (log MRc 0.77) and *1F/*1 A (log MRc 0.82) genotypes compared with the *1 A/*1 A genotype (log MRc 0.71) (anovaP = 0.07). The mean difference between the *1 A homozygotes and the heterozygotes was 0.11 [95% confidence interval of the difference: (-0.21, -0.01)] and that between the *1 A and *1F homozygotes was 0.05 [95% confidence interval of the difference: (-0.13, 0.03)]. No significant effect (P = 0.22) of the *1F on CYP1A2 activity was observed in smokers, tested using an interaction term (smoking * genotype) in the anova model (*1F/*1F log MRc 0.79, *1F/*1 A log MRc 0.86, and *1 A/*1 A log MRc 0.73). In smokers, there was no difference in ratio between homozygotes for the *1 A and *1F alleles [mean difference -0.06; 95% confidence interval of the difference: -0.22, 0.11] or between *1 A/*1 A and *1 A/*1F genotypes [mean difference -0.13; 95% confidence interval of the difference: -0.29, 0.04]. CONCLUSIONS: The effect of the CYP1A2*1F mutation on CYP1A2 activity in smoking pregnant women could not be confirmed. 相似文献
8.
AIMS: To investigate the distribution characteristics of CYP1A2 in a Chinese population, and to examine gender-related differences in CYP1A2 activity. METHODS: Two hundred and twenty-nine healthy subjects, 120 men and 109 women, were enrolled in this study. CYP1A2 activity was measured by plasma paraxanthine/caffeine (1,7X/1,3,7X) ratio 6 h after administration of 300 mg caffeine. The concentrations of paraxanthine and caffeine in plasma were detected by h.p.l.c. RESULTS: A 16-fold variation of CYP1A2 activity (range 0. 09 to 1.46) was shown in this study. The coefficient of variation (CV %) of CYP1A2 activity was 62.9%. Non-normal distribution of CYP1A2 activity was indicated by the Shapiro-Wilk test (P<0.001). Probit plots of CYP1A2 activity revealed a bimodal distribution with breakpoint of 1,7X/1,3,7X ratio of 0.12. The percentage of poor metabolizers (PMs) was 5.24% (95% CI: 2.35% approximately 8.13%) in this Chinese population. Residual analysis of the data also supported bimodality (P<0.01). The CYP1A2 activity of men was higher than that of women (median: 0.33 vs 0.23, P<0.001). A probit plot of CYP1A2 activity in men was shifted to the left compared with that in women. Based on phenotype, the gender-related difference was observed in extensive metabolizers (EMs) (P<0.001), but not in PMs (P >0.1). In addition, there was no sex-related difference in the incidence of PMs (P >0.1). CONCLUSIONS: There is a phenotypic polymorphism in CYP1A2 activity in this Chinese population, and CYP1A2 activity is higher in men than that in women. 相似文献
9.
AIM: To investigate the possible association of the CYP2D6 gene C100T polymorphism and the CYP1A2 gene C163A polymorphism with tardive dyskinesia (TD) in Chinese patients with schizophrenia. METHODS: The recruited schizophrenic patients were assessed with the Abnormal Involuntary Movement Scale (AIMS), and divided into groups with TD (n=91) and without TD (n=91) according to the AIMS score. Polymorphisms of the CYP2D6 and CYP1A2 genes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: No allele frequencies deviated from Hardy-Weinberg equilibrium. No significant differences in genotypes frequencies of the CYP2D6 C100T polymorphism were observed between patients with TD and without TD (Chi2=4.078, P>0.05), but patients with TD had a significant excess of the T allele compared with those without TD (Chi2=4.28, P<0.05). Moreover, the frequency of the CYP1A2 C allele in patients with TD was significantly higher than that in those without TD (Chi2=6.38, P<0.05). An association between TD and the CYP2D6 100T and CYP1A2 163C alleles was observed. Additionally, there were no differences in the mean AIMS scores among different genotypes in TD patients as a group or in smokers. The results of logistic regression analysis demonstrated that mean age and duration of illness were risk factors for TD, but not sex, cumulative exposure to neuroleptic drugs in years, CYP2D6 or CYP1A2 genotype. CONCLUSION: The C100T polymorphism of the CYP2D6 gene and the C163A polymorphism of the CYP1A2 gene may be associated with neuroleptic drug-induced tardive dyskinesia in Chinese patients with schizophrenia. However, genetic factors have a weaker association with susceptibility to TD compared with mean age and duration of illness. 相似文献
10.
AIMS: The aim was to develop a fast detection method for the polymorphic alleles related to impaired CYP2C9-mediated metabolism. METHODS: CYP2C9 genotypes were identified in 118 DNA samples using real-time PCR (LightCycler) followed by melting curve analysis. All samples were re-tested by validated PCR-RFLP methodology. RESULTS: The concordance between the two methods was 100% for two variant alleles. The frequencies of CYP2C9*1 (wild type), CYP2C9*2 and CYP2C9*3 (with 95% confidence intervals) were 0.81(0.05), 0.14(0.04) and 0.05(0.03), respectively, and are similar to those observed in other Caucasian populations. CONCLUSIONS: This assay is simple and rapid and may be used for CYP2C9-genotyping in a clinical setting. 相似文献
11.
AIMS: The cytochrome P450 enzyme CYP1A2 metabolises several drugs and carcinogens. We wanted to determine how much of the variability of CYP1A2 activity is explained by a newly discovered gene polymorphism in intron 1. METHODS: A single nucleotide polymorphism in intron 1 of the CYP1A2 gene at position 734 downstream of the first transcribed nucleotide was identified by DNA sequence analysis. The functional significance of this C/A polymorphism was assessed in 185 healthy Caucasian non-smokers and in 51 smokers by genotyping and phenotyping using caffeine (100 mg oral dose). RESULTS: Out of the total sample, 46% were homozygous for the variant A, 44% were heterozygous, and 10% were homozygous for the variant C. The ratio of 1,7-dimethylxanthine (17X) plus 1,7-dimethyluric acid divided by caffeine in 0-5 h urine samples from 185 non-smokers did not differ significantly between the three CYP1A2 genotypes. In the 51 smokers, analysis of variance revealed significant differences in the 5 h plasma 17X/caffeine ratios between the genotypes (P=0.008, F-test). The mean ratio was 1.37 in carriers of the A/A genotype, 0.88 in heterozygotes and 0.82 in carriers of C/C. The mean difference between the A/A and C/A groups was 0.48 (95% confidence interval 0. 15-0.81; P=0.01). CONCLUSIONS: The A/A genotype, which may represent a CYP1A2 high inducibility genotype, may either be a direct cause of increased CYP1A2 activity, or be genetically linked to polymorphisms conferring high inducibility. Further studies are needed to define the role of this polymorphism on the pharmacokinetics of drugs metabolised by CYP1A2 and in the activation of carcinogens. 相似文献
12.
目的研究复方银杏叶胶囊(CGB)对酒精性肝损伤大鼠CYP2E1、CYP3A4活性的影响。方法正常组和酒精性肝损伤模型组均以CGB[(250 mg/(kg.d)]灌胃,分别在灌胃CGB前及灌胃1周后,灌胃探针药氯唑沙宗(50 mg/kg)及氨苯砜(20 mg/kg),于探针药灌后24 h内不同时间点采血,测定各探针药血药浓度。结果灌胃CGB前,模型组氯唑沙宗和氨苯砜的AUC0-24、Cmax均显著低于正常组(P<0.05或P<0.01)。灌胃CGB后,模型组氯唑沙宗和氨苯砜的AUC0-24、Cmax均较灌胃前显著升高(P<0.05或P<0.01);且氯唑沙宗的t1/2灌胃CGB后明显高于灌胃前(P<0.05)。结论 CGB能够明显抑制酒精性肝损伤大鼠CYP2E1、CYP3A4酶活性。 相似文献
13.
目的:研究中国人群中CYPlA2基因G-2964A和C734A多态性分布.方法:应用聚合酶链反应-限制片长多态性技术对163名启东人和78名长沙人进行基因型分析.结果:等位基因A-2964在启东和长沙人中的发生率分别是0.25和0.22.A734的发生率在启东人中为0.68,而在长沙人中为0.66.一个受试者的两条等位基因中至多含有两个底活性位点.结论:G-2964A和C734A基因多态性在中国人和日本人中的分布没有显著性差异,C734A基因多态性在中国人中的分布也类似于白种人. 相似文献
14.
目的:查明CYP2C9、CYV2C8等抗糖尿病药物主要代谢酶的基因多态性在中国2型糖尿病(T2DM)A-群中的分布频率和分布特征。方法:运用多聚酶链反应.限制性长度多态性(PCR.RFLP)方法和变性高效液相色谱法(DHPLC)对222名中国T2DM患者进行了有功能意义的CYP2C8*3、CYP2C8P404A和CYP2C9*3,以及可能存在功能意义的CYP2C8IVs2(-5insertt)突变体等等位基因型检测,并计算了各等位基因的频率。结果:222名中国T2DM患者的CYP2C8基因中未检出CYP2C8*3、P404A型,CYP2C8IVS2(-5insertt)和CYP2C9*3等位基因的频率分别为43.0%、2.48%,二者突变等位基因在男、女性别分布中不存在差异(P〉0.05),同时为CYP2C8IVS2(-5insertt)和CYP2C9*1*3基因的频率为6.3%,该联合突变基因型的分布也不存在性别差异(P〉0.05)。结论:中国T2DM患者中CYP2C9*3的等位基因频率为2.48%;未检出CYP2C8。3和P404A型,CYP2C81VS2(-5insertt)突变体发生频率为43.0%,其是否影响CYV2C8的代谢活力有待于进-步研究。 相似文献
15.
Objective: The aim of the present study was to investigate the distribution of the CYP2D6 and GSTM1 genotypes in a Polish population.
Methods: One hundred and forty-five unrelated healthy individuals from the western region of Poland were studied. The CYP2D6 genotype was analysed by means of polymerase chain reaction (PCR) amplification for the CYP2D6
*
3 and CYP2D6
*
4 alleles. The GSTM1 genotype was also analysed by means of a PCR assay to determine two genotypes: GSTM1-1 (positive) and GSTM1-0 (negative).
Results: Fourteen subjects (9.6%) were classified as poor metabolisers. The frequency of CYP2D6
*
4 and CYP2D6
*
3 was 23.1% and 2.1%, respectively. The frequency of GSTM1 nulled genotype in a Polish population came to 49%.
Conclusion: The frequencies of poor metabolisers for CYP2D6 and GSTM1 nulled genotype among a Polish population were similar to those observed in other Caucasian populations.
Received: 29 October 1998 / Accepted in revised form: 15 March 1999 相似文献
16.
AIMS: The goal of this study was to determine the frequencies of CYP1A2*1C, *1D, *1E and *1F variants in the Egyptian population and compare frequencies with other populations. METHODS: Genotyping was performed in a total of 212 unrelated Egyptian subjects using polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: The frequencies of CYP1A2*1C, *1D, *1E and *1F variants in the Egyptian population were 0.07, 0.40, 0.03 and 0.68, respectively. The Egyptians have a lower frequency of CYP1A2*1C, and CYP1A2*1E than the Japanese (0.07 vs 0.21 and 0.03 vs 0.08, respectively), while the frequencies of CYP1A2*1D and CYP1A2*1F did not differ significantly between the two groups. CYP1A2*1F (0.68) frequency in Egyptians was identical to that observed in Caucasians (0.68 among 236 German individuals). CONCLUSIONS: The present study is the first to describe the frequencies of four known allelic variants of CYP1A2 among the Egyptian population. CYP1A2*1C and *1E occurred at frequencies significantly lower than that in Japanese, while similar frequencies were observed for CYP1A2*1D and *1F. The CYP1A2*1F frequency appeared to be identical to that of Caucasians. This does not exclude the possibility of the presence of new mutations relatively specific to the Egyptian population that have not been identified. 相似文献
17.
目的:在人体内研究止咳橘红对CYP3A4和CYP1A2的抑制作用,以预测止咳橘红与常用临床药物的相互作用。方法:咪哒唑仑和咖啡因分别作为CYP3A4和A2的探针药物,采取交叉设计,10名受试者在服用3d止咳橘红的前后均服用7.5mg咪哒唑仑和100mg咖啡因,服药后采血测定两者及代谢产物的代谢动力学参数,探讨针药物及代谢物的浓度用HPLC-MS法测定,Cmax,tmax从药时曲线中直接读出,AUC用梯形法计算,Ke用3P87程序进行拟合计算,分析服药前后CYP3A4和CYP1A2被抑制的情况,结果 服用止咳橘红后,咪哒唑仑的代谢受到了轻微的抑制,它的血药浓度,达峰时间和药时曲线下面积都有了升高趋势,但无显著差异。而咖啡因的代谢未受到影响。结论 止咳橘红对CYP3A4的活性有较弱的抑制作用,能够导致CYP3A4底物咪哒唑仑代谢的轻微抑制,而对CYP1A2的活性没有影响。止咳橘红长期使用或超过治疗剂量使用时是否会对CYP3A4产生显著性影响。尚需进一步的研究证明。 相似文献
18.
目的研究慢性间断性低氧对大鼠肝脏CYP3A2和CYP2E1的影响。方法将大鼠随机分为对照组、低氧3d组、低氧7d组、低氧14d组、低氧28d组,低氧处理结束24h后,常规腹腔注射麻醉,摘取眼球血液2ml制备血清,并测定丙氨酸氨基转移酶(ALT)、天门冬酸氨基转移酶(AST)、红霉素N-脱甲基酶(ERD)、苯胺羟化酶(ANH)活性;取新鲜肝组织以制备微粒体和提取核糖核酸(RNA),并以RT-PCR进行基因片段扩增以检测大鼠肝脏细胞色素CYP3A2、CYP2E1的mRNA表达水平。结果慢性间断性低氧对血清ALT、AST活性无明显影响;低氧7d后,大鼠肝脏ERD、ANH活性明显升高,28d时诱导率分别为155.5%、42.2%;同时,CYP3A2、CYP2E1mRNA的表达水平也分别增加了220.5%、102.8%。结论慢性间断性低氧能显著增加大鼠肝脏ERD、ANH活性,其机制可能与其在转录水平上提高肝脏CYP3A2和CYP2E1的基因表达水平有关。 相似文献
19.
AIMS: Several single nucleotide polymorphisms (SNPs) of the cytochrome P450 enzyme 1A2 gene (CYP1A2) have been reported. Here, frequencies, linkage disequilibrium and phenotypic consequences of six SNPs are described. METHODS: From genomic DNA, 114 British Caucasians (49 colorectal cancer cases and 65 controls) were genotyped for the CYP1A2 polymorphisms -3858G-->A (allele CYP1A2*1C), -2464T-->delT (CYP1A2*1D), -740T-->G (CYP1A2*1E and *1G), -164A-->C (CYP1A2*1F), 63C-->G (CYP1A2*2), and 1545T-->C (alleles CYP1A2*1B, *1G, *1H and *3), using polymerase chain reaction-restriction fragment length polymorphism assays. All patients and controls were phenotyped for CYP1A2 by h.p.l.c. analysis of urinary caffeine metabolites. RESULTS: In 114 samples, the most frequent CYP1A2 SNPs were 1545T-->C (38.2% of tested chromosomes), -164A-->C (CYP1A2*1F, 33.3%) and -2464T-->delT (CYP1A2*1D, 4.82%). The SNPs were in linkage disequilibrium: the most frequent constellations were found to be -3858G/-2464T/-740T/-164A/63C/1545T (61.8%), -3858G/-2464T/-740T/-164C/63C/1545C (33.3%), and -3858G/-2464delT/-740T/-164A/63C/1545C (3.51%), with no significant frequency differences between cases and controls. In the phenotype analysis, lower caffeine metabolic ratios were detected in cases than in controls. This was significant in smokers (n = 14, P = 0.020), and in a subgroup of 15 matched case-control pairs (P = 0.007), but it was not significant in nonsmokers (n = 100, P = 0.39). There was no detectable association between CYP1A2 genotype and caffeine phenotype. CONCLUSIONS: (i) CYP1A2 polymorphisms are in linkage disequilibrium. Therefore, only -164A-->C (CYP1A2*1F) and -2464T-->delT (CYP1A2*1D) need to be analysed in the routine assessment of CYP1A2 genotype; (ii) in vivo CYP1A2 activity is lower in colorectal cancer patients than in controls, and (iii) CYP1A2 genotype had no effect on phenotype (based on the caffeine metabolite ratio). However, this remains to be confirmed in a larger study. 相似文献
20.
AbstractEnzyme kinetic parameters provide essential quantitative information about characterization of individual steps in drug metabolism. Such enzymes are located in a (partially) aqueous environment. For in vitro measurements potential lipophilic substrates regularly require organic solvents to achieve concentrations sufficient for access of the drug to the binding site of the enzyme. However, solvents may interact with the enzymes. In this study, we investigated the effects of methanol, ethanol, acetonitrile and dimethyl sulfoxide (1% to 4%) on the assessment of k m, V max and Cl int for the metabolism of midazolam via CYP3A4 to 1-hydroxymidazolam and the metabolism of caffeine to paraxanthine via CYP1A2 using expressed enzymes in vitro. The presence of acetonitrile proved the highest apparent V max value for paraxanthine formation but the lowest values for 1-hydroxymidazolam formation. The k m value for midazolam showed no systematic effects of organic solvents, while for caffeine k m was up to 8-fold lower for solvent free samples compared to solvent containing samples. The present example suggests that effects of solvents may considerably influence enzyme kinetic parameters beyond a mere change in apparent activity. These effects illustrate a difference for individual enzyme--substrate pairs, solvents, and solvent concentrations. What remains is the determination to which extent these effects compromise in vitro–in vivo extrapolations, and which solvents are most appropriate. 相似文献
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