Human CYP1A2 is one of the major CYPs in human liver and metabolizes a number of clinical drugs (e.g., clozapine, tacrine, tizanidine, and theophylline; n > 110), a number of procarcinogens (e.g., benzo[a]pyrene and aromatic amines), and several important endogenous compounds (e.g., steroids). CYP1A2 is subject to reversible and/or irreversible inhibition by a number of drugs, natural substances, and other compounds. The CYP1A gene cluster has been mapped on to chromosome 15q24.1, with close link between CYP1A1 and 1A2 sharing a common 5'-flanking region. The human CYP1A2 gene spans almost 7.8 kb comprising seven exons and six introns and codes a 515-residue protein with a molecular mass of 58,294 Da. The recently resolved CYP1A2 structure has a relatively compact, planar active site cavity that is highly adapted for the size and shape of its substrates. The architecture of the active site of 1A2 is characterized by multiple residues on helices F and I that constitutes two parallel substrate binding platforms on either side of the cavity. A large interindividual variability in the expression and activity of CYP1A2 has been observed, which is largely caused by genetic, epigenetic and environmental factors (e.g., smoking). CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR) and CYP1A2 is induced through AhR-mediated transactivation following ligand binding and nuclear translocation. Induction or inhibition of CYP1A2 may provide partial explanation for some clinical drug interactions. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of them have been associated with altered drug clearance and response and disease susceptibility. Further studies are warranted to explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.

Human CYP1A2 is one of the major CYPs in human liver and metabolizes a variety of clinically important drugs (e.g., clozapine, tacrine, tizanidine, and theophylline), a number of procarcinogens (e.g. benzo[a]pyrene and aflatoxin B(1)), and several important endogenous compounds (e.g. steroids and arachidonic acids). Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds, which may provide an explanation for some drug interactions observed in clinical practice. A large interindividual variability in the expression and activity of CYP1A2 and elimination of drugs that are mainly metabolized by CYP1A2 has been observed, which is largely caused by genetic (e.g., SNPs) and epigenetic (e.g., DNA methylation) and environmental factors (e.g., smoking and comedication). CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR) and CYP1A2 is induced through AhR-mediated transactivation following ligand binding and nuclear translocation. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of they have been associated with altered drug clearance and response to drug therapy. For example, lack of response to clozapine therapy due to low plasma drug levels has been reported in smokers harboring the -163A/A genotype; there is an association between CYP1A2*1F (-163C>A) allele and the risk for leflunomide-induced host toxicity. The *1F allele is associated with increased enzyme inducibility whereas *1C causes reduced inducibility. Further studies are warranted to explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.

The G protein-coupled receptors LGR7 and LGR8 have recently been identified as the primary receptors for the polypeptide hormone relaxin and relaxin-like factors. RT-PCR confirmed the existence of mRNA for both LGR7 and LRG8 in THP-1 cells. Whole cell treatment of THP-1 cells with relaxin produced a biphasic time course in cAMP accumulation, where the first peak appeared as early as 1-2 min with a second peak at 10-20 min. Selective inhibitors for phosphoinositide 3-kinase (PI3K), such as wortmannin and LY294002, showed a dose-dependent inhibition of relaxin-mediated increases in cAMP, specific for the second peak of the relaxin time course. Adenylyl cyclase activation by relaxin in purified plasma membranes from THP-1 cells was not inhibited by LY294002, consistent with a mechanism involving direct stimulation by a Galphas-coupled relaxin receptor. However, reconstitution of membranes with cytosol from THP-1 cells enhanced adenylyl cyclase activity and restored LY294002 sensitivity. In addition, relaxin increased PI3K activity in THP-1 cells. Neither the effects of relaxin nor the inhibition of relaxin by LY294002 was mediated by the activity of phosphodiesterases. Taken together, we show that PI3K is required for the biphasic stimulation of cAMP by relaxin in THP-1 cells and present a novel signal transduction pathway for the activation of adenylyl cyclase by a G protein-coupled receptor.

Human CYP2C8 is a key member of the CYP2C family and metabolizes more than 60 clinical drugs. A number of active site residues in CYP2C8 have been identified based on homology modeling and site-directed mutagenesis studies. In the structure of CYP2C8, the large active site cavity exhibits a trifurcated topology that approximates a T or Y shape, which is consistent with the finding that CYP2C8 can efficiently oxidize relatively large substrates such as paclitaxel and cerivastatin. The active site cavity of CYP2C8 contains at least 48 amino acid residues and many of them are important for substrate binding. The structures of CYP2C8 in complex with distinct ligands have revealed that the enzyme can bind divergent substrates and inhibitors without extensive conformational changes. CYP2C8 is a major catalyst in the metabolism of paclitaxel, amodiaquine, troglitazone, amiodarone, verapamil and ibuprofen, with a secondary role in the biotransformation of cerivastatin and fluvastatin. CYP2C8 also metabolises endogenous compounds such as retinoids and arachidonic acid. Many drugs are inhibitors of CYP2C8 and inhibition of this enzyme may result in clinical drug interactions. The pregnane X receptor, constitutive androstane receptor, and glucocorticoid receptor are likely to involve the regulation of CYP2C8. A number of genetic mutations in the CYP2C8 gene have been identified in humans and some of them have functional impact on the clearance of drugs. Further studies are needed to delineate the role of CYP2C8 in drug development and clinical practice.

ObjectivePrecise genetic analyses were conducted with ring finger protein 213 (RNF213) in relation to a particular clinical phenotype in Chinese patients with moyamoya disease (MMD) to determine whether heterozygosity is responsible for the early-onset and severe form of this disease.MethodsA case–control study for RNF213 p.R4810K involving 1,385 Chinese patients with MMD and 2,903 normal control participants was performed. Correlation analyses between genotype and phenotype or different clinical features were also statistically explored.ResultsAn obvious trend was observed: the carrying rate of RNF213 p.R4810K gradually decreased when moving from coastal cities in northeast, north, and east China to southern cities or inland areas. Higher frequencies of p.R4810K were observed in patients with MMD compared with control participants (odds ratio, 48.1; 95% confidence interval, 29.1–79.6; p = 1.6 × 10−141). In addition, the onset age of all patients with the GA and AA genotypes were lower than with the GG genotype, and the median onset age was 40.0, 36.0, and 11.5 years with GG, GA, and AA, respectively, thereby confirming that those with GA or AA could acquire MMD during early life stages. Patients with MMD with the GA genotype were more susceptible to posterior cerebral artery (PCA) involvement compared to those with the GG genotype (38.4% vs 23.3%, p = 8.3 × 10−7).ConclusionsStrong evidence suggests that the carrying rate of RNF213 p.R4810K is closely related MMD risk in China and has given rise to an earlier onset age and more severe PCA involvement.

Diabetes has been a disease of public health concern for a number of decades. It was in the 1930s when scientists made an interesting discovery that the disease is actually divided into two types as some patients were insensitive to insulin treatment then. Type 2 Diabetes which happens to be the non-insulin dependent one is the most common form of the disease and is caused by the interaction between genetic and non-genetic factors. Despite conflicting results, numerous studies have identified genetic and non-genetic factors associated with this common type of diabetes. This review has summarized literature on some genes and non-genetic factors which have been identified to be associated with Type 2 diabetes. It has sourced literature from PubMed, Web of Science and Medline without any limitation to regions, publication types, or languages. The paper has started with the introduction, the play of non-genetic factors, the impact of genes in general, and ended with the interaction between some genes and environmental factors.

CYP2C9 is one of the most abundant CYP enzymes in the human liver ( approximately 20% of hepatic total CYP content). CYP2C9 metabolizes approximately 20% clinical drugs (>120 drugs), including a number of drugs with narrow therapeutic ranges. Some natural compounds are also metabolized, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Typical substrates of CYP2C9 such as celecoxib, ibuprofen, flurbiprofen, and diclofenac are relatively small, lipophilic and contain acidic groupings with pK(a) values in the range 3.8-8.1 which will be ionized at physiological pH. The carboxylate groups of tienilic acid and diclofenac have been shown to be responsible for substrate preference and orientation in the active site of CYP2C9. Therefore, a typical CYP2C9 substrate should contain an anionic site and a hydrophobic site. However, neutral or positively charged compounds may also be substrates of CYP2C9. CYP2C9 is subject to inhibition by a number of drugs and other compounds and this may provide an explanation for some clinical drug-drug interactions. With regard to prodrugs that need CYP2C9 for activation, inhibition of CYP2C9 may cause a decrease in the amount of the active metabolite, leading to therapeutic failure. Pharmacophore models have revealed that hydrogen bonding, ion-pair interactions, and probably hydrophobic interactions play a major role in determining the substrate specificity and inhibitor selectivity of CYP2C9. A number of structure-activity relationship studies have identified the structural determinants of compounds for their binding affinity to CYP2C9 and inhibitory potency for CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates and/or inhibitors of CYP2C9 in drug development and drugs with minimal interactions with this enzyme should be chosen for further development. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

Background and Purpose— A growing body of evidence indicates genetic components play critical roles in moyamoya disease (MMD). Firm conclusions from studies of this disease have been stymied by small sample sizes and a lack of replicative results. This meta-analysis was conducted to determine whether these genetic polymorphisms are associated with MMD. Methods— PubMed, Google Scholar, Embase, Wanfang, Web of Science, and China National Knowledge Infrastructure databases were used to identify potentially relevant studies published until January 2020. The Review Manager 5.2 and Stata 15.0 software programs were used to perform the statistical analysis. Heterogeneity was assessed using the Cochran Q test and quantified using the I 2 test. Results— Four thousand seven hundred eleven MMD cases and 8704 controls in 24 studies were included, evaluating 7 polymorphisms in 6 genes. The fixed-effect odds ratios (95% CI) in allelic model of MMP-2 rs243865 were 0.60 (0.41–0.88) ( P =0.008). In the country-based subgroup analysis, the fixed-effect odds ratios (95% CI) of RNF213 rs112735431 in allelic model were China, 39.74 (26.63–59.31), Japan, 74.65 (42.79–130.24) and Korea, 50.04 (28.83–86.88; all P <0.00001). In the sensitivity analysis, the fixed-effect odds ratios (95% CI) of allelic and dominant models were the RNF213 rs148731719 variant, 2.17 (1.36–3.48; P =0.001), 2.20 (1.35–3.61; P =0.002), the TIMP-2 rs8179090 variant, 0.33 (0.25–0.43; P <0.00001), 0.88 (0.65–1.21; P =0.440) and the MMP-3 rs3025058 variant, 0.61 (0.47–0.79; P =0.0002), 0.55 (0.41–0.75; P =0.0001), respectively. Conclusions— RNF213 rs112735431 and rs148731719 were positively, and TIMP-2 rs8179090, MMP-2 rs243865, and MMP-3 rs3025058 were inversely associated with MMD using multiple pathophysiologic pathways. Studies in larger population should be conducted to clarify whether and how these variants are associated with MMD.