No abstract

The let-7 family is the second microRNA found in C. elegans. Recent researches have found it is highly expressed in the cardiovascular system. Studies have revealed the aberrant expression of let-7 members in cardiovascular diseases, such as heart hypertrophy, cardiac fibrosis, dilated cardiomyopathy (DCM), myocardial infarction (MI), arrhythmia, angiogenesis, atherosclerosis, and hypertension. Let-7 also participates in cardiovascular differentiation of embryonic stem cells. TLR4, LOX-1, Bcl-xl and AGO1 are by now the identified target genes of let-7. The circulating let-7b is suspected to be the biomarker of acute MI and let-7i, the biomarker of DCM. Further studies are necessary for identifying the gene targets and signaling pathways of let-7 in cardiovascular diseases. Let-7 might be a potential therapeutic target for cardiovascular diseases. This review focuses on the research progresses regarding the roles of let-7 in cardiovascular development and diseases.

Our data indicate that the presence of the CYP2C19*17 allele results in ultra-rapid metabolism of voriconazole after a single oral dose.

We examined genetically determined oxidation polymorphisms of metoprolol and mephenytoin in 200 unrelated, healthy Japanese subjects and in 98 mainland Chinese subjects simultaneously. This examination was done according to the respective reported phenotyping criteria by use of the urinary metabolic ratio of metoprolol and of the percentage of excretion of 4-hydroxymephenytoin 8 hours after dose administration. The frequencies of occurrence of poor metabolizers (PMs) in the Japanese versus the Chinese subjects were 0.5% versus 0% for metoprolol and 22.5% versus 17.4% for mephenytoin, respectively. There were no statistically significant differences in these frequencies between the two Oriental populations. However, Chinese extensive metabolizers (EMs) showed a significantly lower excretion of alpha-hydroxymetoprolol (p less than 0.01) and 4-hydroxymephenytoin (p less than 0.001) than that of Japanese EMs, and the mode of the distribution histogram of the Chinese EMs for the two test probes was skewed compared with that of the Japanese EMs. The findings indicate that the two Far Eastern Oriental subject groups have a lower frequency of PM phenotype of debrisoquin/sparteine-type oxidation and a greater incidence of PM phenotype of mephenytoin oxidation compared with the respective frequencies reported from white subjects. However, the explanation for the observation that the metabolic capacities of the test drugs differed between the EMs of the two populations who had a similar ethnic origin and who resided in the same geographic area remains obscure.

Carvedilol is a mixed alpha- and beta-adrenergic receptor antagonist that is administered as a racemic mixture. Although the two isomers are equally potent as alpha 1-blockers the S(-)-isomer is principally responsible for the beta blockade of carvedilol. To determine the role of pharmacogenetics in the metabolism of carvedilol we studied nine extensive metabolizers of both debrisoquin and mephenytoin, seven poor metabolizers of debrisoquin but extensive metabolizers of mephenytoin, and three poor metabolizers of mephenytoin but extensive metabolizers of debrisoquin. The clearance of R-carvedilol was significantly lower than S-carvedilol in both debrisoquin phenotypes. Poor metabolizers of debrisoquin had a significantly lower clearance of R-carvedilol than extensive metabolizers of debrisoquin. The partial metabolic clearance of carvedilol to the two ring-hydroxylated metabolites 4- and 5-hydroxyphenyl carvedilol were significantly reduced in poor metabolizers of debrisoquin. No effect of mephenytoin phenotype on carvedilol kinetics was observed. Thus carvedilol is stereoselectively metabolized in humans, and the clearance of S-carvedilol is higher than that of R-carvedilol. In poor metabolizers of debrisoquin the clearance of R-carvedilol is further reduced, resulting in higher plasma concentrations and perhaps greater alpha-blockade.

The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, and both extensive and poor metabolizers had marked differences in the disposition of sertraline.

Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

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%~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.Keywords: caffeine, cytochrome P1A2, cytochrome P450, gender-related differences, pharmacogenetics, polymorphism intermediates or ultimate carcinogens [5]. Individual Introduction variation in CYP1A2 is relevant to drug efficacy, adverse reactions and susceptibility to certain carcinoma [5][6][7]. CYP1A2 is an important member of the cytochrome P450 superfamily [1]. The coding gene CYP1A2, whichIn vivo activity of CYP1A2 can be measured by administration of probe drugs such as caffeine, phenacetin locates on chromosome 15 in humans, contains 6 introns and 7 exons, and the gene length is about 7.8 kb.and theophylline [5,6,8]. Presently, caffeine is the most commonly used probe because of its low toxicity and CYP1A2 is mainly expressed in human liver and the protein content of CYP1A2 contributes 13% of the total good acceptance [8]. Nine enzymes including CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A4, CYP protein in liver [2]. CYP1A2 activity can be used to monitor the alteration of liver function in clinical CYP3A5, NAT2 and XO (xanthine oxidase) are involved in the metabolism of caffeine and at least 14 metabolites practice [3]. CYP1A2 is involved in the metabolism of many clinical drugs, environmental toxins and endogenare formed by demethylation and hydroxylation [8].Of all the metabolic pathways, caffeine 3-demethylation ous substrates [4,5]. It may play a critical role in the activation of a wide range of procarcinogens to genotoxic is the most prominent reaction accounting for 80% of sys...