Guo-Lin Chen

The Influence of St. John's Wort on CYP2C19 Activity with Respect to Genotype

Induction of cytochrome P450 isozymes is the major cause for clinical drug interactions of St. Johns wort. The relationships of St. Johns wort to cytochrome P450 isoforms have been fully investigated, but its effect on CYP2C19 is lacking. Thus, the aim of the present study was to observe the effect of St. Johns wort on CYP2C19 activity using CYP1A2 as a control. Twelve healthy adult men—6 extensive metabolizers of CYP2C19 (2C19*1/2C19*1) and 6 poor metabolizers (4 2C19*2/ 2C19*2 and 2 2C19*2/2C19*3)—were enrolled in a two‐phase, randomized, crossover manner. All subjects took a 300‐mg St. Johns wort tablet or placebo three times daily for 14 days, and then the activities of CYP2C19 and CYP1A2 were measured using mephenytoin and caffeine. It was found that St. Johns wort treatment significantly increased CYP2C19 activity in CYP2C19 wild‐genotype subjects, with urinary 4′‐hydroxymephenytoin excretion raised by 151.5% ± 91.9% (p = 0.0156), whereas no significant alteration was observed for CYP2C19 poor metabolizers. Repeated St. Johns wort administration did not affect the CYP1A2 phenotypic ratio for both CYP2C19 genotype subjects. In conclusion, St. Johns wort is an inducer to the human CYP2C19, and clinicians should pay great attention when St. Johns wort is added to or withdrawn from an existing drug regimen containing substrates for such enzymes.

Genotype-phenotype correlation for histamine N-methyltransferase in a Chinese Han population

BACKGROUND Two potential single-nucleotide polymorphisms (SNP) (C314T and A595G) exist in the gene for human histamine N-methyltransferase (HNMT). METHODS A radiochemical microassay was used to measure the erythrocyte HNMT activities, whereas the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed to perform the genetic analysis in 247 unrelated Chinese Han subjects. RESULTS All subjects had detectable HNMT activity. The activity of HNMT was gender related (males>females, p<0.0001), with a 5.5-fold individual variation. The distribution of HNMT activity was compatible with a normal distribution. There were 28 heterozygotes for the variant T314 allele among the 247 subjects, whereas no A595G transition was observed. All heterozygotes for the T314 allele displayed an intermediate or low HNMT activity, with an average HNMT activity being 34.0% lower than those with wild-type genotype (623.1+/-136.0 vs. 944.8+/-249.3 U/ml red blood cells [RBC], p<0.0001). CONCLUSION The C314T polymorphism was functionally important and contributes in part to phenotypic variance of HNMT activity in Chinese Han population. Additional unknown genetic or epigenetic factors should also play important roles in the regulation of HNMT activity.

Single nucleotide polymorphisms and haplotypes of histamine N-methyltransferase in patients with gastric ulcer

Abstract.Introduction: Histamine plays a crucial role in the regulation of gastric acid secretion, which is involved in the pathogenesis of peptic ulcer. Histamine N-methyltransferase (HNMT) is the major metabolizing enzyme for histamine inactivation in human stomach.Objective: This study aims to determine whether there exists a relationship between HNMT gene polymorphisms and the risk for gastric ulcer (GU).Methods: 118 GU patients and 154 ethnically matched control subjects were enrolled and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays were developed to genotype all these subjects for the T-1637C, C-411T, C314T and A1097T point mutations in HNMT gene. Haplotypes were reconstructed from the genotype data.Results: Frequencies of the variant alleles in cases and controls were 0.398 vs 0.396 for T-1637C, 0.144 vs 0.110 for C-411T, 0.034 vs 0.042 for C314T, and 0.242 vs 0.273 for A1097T, respectively, with no significant difference for any locus between the two groups (all P > 0.05). Also the frequencies of genotypes, haplotypes and haplotype pairs based on these polymorphisms did not differ significantly between cases and controls.Conclusion: This study provided no evidence for the involvement of HNMT polymorphisms in the susceptibility to GU.

Analysis of the C314T and A595G mutations in histamine N-methyltransferase gene in a Chinese population.

BACKGROUND Histamine N-methyltransferase (HNMT) plays an important role in the metabolism of histamine, a biogenic amine that has many physiologic and pathological roles in human tissues. A missense mutation C314T (Thr105Ile) in the HNMT gene has been identified to represent a common functional polymorphism in Caucasians, whereas an A595G (Ile199Val) variant has been reported in one HNMT cDNA from a Japanese subject. METHODS By using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, the point mutations C314T and A595G within HNMT were both detected in 352 unrelated Chinese Han subjects. RESULTS None of the 352 subjects contained the A595G mutation, whereas 40 (11.6%) heterozygotes and 1 (0.3%) homozygote for the variant T314 allele were detected. The frequency of the variant T314 allele in this Chinese population was 0.060 (95% CI: 0.042-0.078), not different from Japanese but significantly lower than American Caucasians. CONCLUSIONS The C314T mutation represents a common functional genetic polymorphism in the Chinese Han population with a variant T314 allele frequency similar to Japanese but lower than American Caucasians, whereas the A595G mutation does not appear to exist in this population.

Endogenous histamine and cortisol levels in subjects with different histamine N-methyltransferase C314T genotypes : a pilot study.

AbstractBackground: Histamine N-methyltransferase (HNMT) catalyzes the methylation of histamine and plays an important role in histamine biotransformation in bronchial epithelium. Enzymatic activity of HNMT has been shown to be regulated by genetic factors, including polymorphisms in the HNMT gene. In this pilot study we determined endogenous levels of histamine and cortisol in plasma and whole blood samples from subjects with different genotypes for the HNMT C314T polymorphism, and investigated whether these parameters differed between individuals with the HNMT CC genotype and those with the CT genotype. Methods: Blood samples were collected from 48 unrelated volunteers (36 males, 12 females), aged 21–40 years, who participated in the study. PCR-restriction fragment length polymorphism analysis was used to determine HNMT C314T genotypes. Erythrocyte HNMT activity was determined as well as plasma and whole blood levels of histamine and cortisol. Two-group comparisons of the various parameters were analyzed by Blocked Wilcoxon test and Wilcoxon Rank Sum test as appropriate. Results: Thirty-seven subjects (24 Caucasians, three African Americans, one Middle Eastern, five Indians, three Chinese, and one Filipino) were found to have the homozygous CC genotype. Ten subjects (eight Caucasians, one Middle Eastern, and one Chinese) were heterozygous and one individual (Pakistani) was homozygous for the variant 314T allele. The frequency of HNMT CI heterozygotes in the small Caucasian cohort was 0.125. Median enzyme activity was significantly lower in subjects with the heterozygous CT genotype than in those with the homozygous CC genotype (485 vs 631 U/mL of red blood cells; p = 0.023). A broad range of histamine levels in plasma and whole blood was observed for all subjects. Whereas the median plasma histamine level was found to be higher in heterozygotes for the wild-type 314C allele than homozygotes (3.32 vs 2.30 nmol/L; p = 0.021), there was no difference between the two groups in histamine levels in whole blood. Cortisol levels were similar between individuals with the homozygous CC genotype and those with the heterozygous CT genotype. Conclusion: Wide variability of plasma and whole-blood histamine levels was observed in subjects with different HNMT C314T genotypes. Endogenous levels of histamine are likely to be affected by various genes and polymorphisms.