To date, the crystal structures of at least 12 human CYPs (1A2, 2A6, 2A13, 2C8, 2C9, 2D6, 2E1, 2R1, 3A4, 7A1, 8A1, and 46A1) have been determined. CYP2D6 accounts for only a small percentage of all hepatic CYPs (< 2%), but it metabolizes approximately 25% of clinically used drugs with significant polymorphisms. CYP2D6 also metabolizes procarcinogens and neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, and indolealkylamines. Moreover, the enzyme utilizes hydroxytryptamines and neurosteroids as endogenous substrates. Typical CYP2D6 substrates are usually lipophilic bases with an aromatic ring and a nitrogen atom, which can be protonated at physiological pH. Substrate binding is generally followed by oxidation (5-7 A) from the proposed nitrogen-Asp301 interaction. A number of homology models have been constructed to explore the structural features of CYP2D6, while antibody studies also provide useful structural information. Site-directed mutagenesis studies have demonstrated that Glu216, Asp301, Phe120, Phe481, and Phe483 play important roles in determining the binding of ligands to CYP2D6. The structure of human CYP2D6 has been recently determined and shows the characteristic CYP fold observed for other members of the CYP superfamily. The lengths and orientations of the individual secondary structural elements in the CYP2D6 structure are similar to those seen in other human CYP2 members, such as CYP2C9 and 2C8. The 2D6 structure has a well-defined active-site cavity located above the heme group with a volume of approximately 540 A(3), which is larger than equivalent cavities in CYP2A6 (260 A(3)), 1A2 (375 A(3)), and 2E1 (190 A(3)), but smaller than those in CYP3A4 (1385 A(3)) and 2C8 (1438 A(3)). Further studies are required to delineate the molecular mechanisms involved in CYP2D6 ligand interactions and their implications for drug development and clinical practice.

The CYP2A6 gene spans a region of approximately 6 kb pairs consisting of 9 exons and has been mapped to the long arm of chromosome 19 (between 19q12 and 19q13.2). The CYP2A6 protein has 494 amino acids and is an important hepatic Phase I enzyme that metabolizes approximately 3% of therapeutic drugs (n > 30; e.g. valproic acid, pilocarpine, tegafur, fadrozole, ifosfamide, cyclophosphamide, nicotine, tamoxifen, promazine, propofol, and cisapride), environmental toxicants (e.g. gasoline additives), and many procarcinogens such as nitrosamines and aflatoxin B(1). This enzyme also participates in the biotransformation of several endogenous compounds such as retinoid acids and steroids. Because CYP2A6 is responsible for 70-80% of the initial metabolism of nicotine, CYP2A6 has been proposed to be a novel target for smoking cessation. Site-directed mutagenesis and homology modeling studies have identified a number of amino acids (e.g. F300, A301, S208, S369, and L370) that play a role in substrate recognition and binding. CYP2A6 shows a crystal structure with a compact, hydrophobic active site with Asn297 serving as one hydrogen bond donor and orienting substrates for regio-selective oxidation. CYP2A6 contains the second smallest active site cavity among the human CYPs with known structures. The regulation mechanism of CYP2A6 expression is not fully understood, but available data suggest that several nuclear receptors including constitutive androstane receptor, pregnane X receptor and glucocorticoid receptor are involved in its regulation. Pilocarpine and tranylcypromine are commonly used as selective competitive inhibitors of CYP2A6. Selegiline, methoxsalen, (R)-(+) menthofuran and decursinol angelate are mechanism-based inhibitors of CYP2A6. Both in vitro and in vivo studies have demonstrated a wide (20- to >100-fold) interindividual variation in CYP2A6 expression and activity, which is due primarily to genetic polymorphisms in the CYP2A6 gene, but CYP2A6 activity is also modified by certain drugs and pathological and environmental factors. To date, more than 36 variant alleles (*1B through *37) of the CYP2A6 gene have been identified. There have been 278 SNPs found in the CYP2A6 upstream sequence, 8 introns and 9 exons in NCBI dbSNP. Polymorphism of CYP2A6 has been associated with smoking behavior, drug clearance and lung cancer risk. Further studies are warranted to explore the role of CYP2A6 in clinical practice, drug development and toxicology.

Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, 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. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of 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, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

Purpose. To investigate the prevalence and some related factors about irritable bowel syndrome (IBS) in medical students. Methods. A cross-sectional study was carried out from February 2014 to Jun 2014 in Beijing University of Chinese Medicine, Beijing, China. All participants were asked to completed self-administered questionnaires. Results. Seven hundred and sixty-seven medical students (23.26 ± 2.88 years, 25.6% males) completed the survey. The prevalence of IBS was 33.3%, with a high prevalence in women (36.1%). Among the IBS patients, 112 cases were IBS-M (43.9%) and 77.6% had moderately severe IBS. There were no statistical differences between control group and IBS patients in anxiety and depression scores (P > 0.05). The total score of Pittsburgh sleep quality index (PSQI) was significantly higher for medical students with IBS and 35.5% of IBS patients had severe sleep disorder; the scores of child trauma questionnaire (CTQ) and student-life stress inventory (SLSI) were also higher in IBS patients. Sex and sleep disorder were independently associated with IBS (OR, 1.914, 95%CI, 1.281–2.860; OR, 1.143, 95%CI, 1.074–1.216). Conclusion. Our study has many valuable findings and they may provide valuable suggestions for the necessary intervention and treatment measures towards medical students.