Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1–3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

Reduced mechanical stress leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes have been identified as major cells responsible for mechanotransduction; however, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. In this study, we found that mechanical unloading of wildtype mice caused decrease of Wnt/β-catenin signaling activity accompanied by upregulation of Sost. To further analyze the causal relationship among these events, Sost gene targeting mice were generated. We showed that sclerostin selectively inhibited Wnt/β-catenin in vivo, and sclerostin suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Interestingly, Sost−/− mice were resistant to mechanical unloading-induced bone loss. Reduction in bone formation in response to unloading was also abrogated in the mutant mice. Moreover, in contrast to wildtype mice, Wnt/β-catenin signaling was not altered by unloading in Sost−/− mice. Those data implied that sclerostin played an essential role in mediating bone response to mechanical unloading, likely through Wnt/β-catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis.

Molecular genetic investigations of attention deficit hyperactivity disorder (ADHD) have found associations with a variable number of tandem repeat (VNTR) situated in the 3′-untranslated region of dopamine transporter gene ( DAT1 ), a VNTR in exon 3 of dopamine receptor 4 gene ( DRD4 ) and a microsatellite polymorphism located at 18.5 kb from the 5′ end of dopamine receptor 5 gene ( DRD5 ). A number of independent studies have attempted to replicate these findings but the results have been mixed, possibly reflecting inadequate statistical power and the use of different populations and methodologies. In an attempt to clarify this inconsistency, we have combined all the published studies of European and Asian populations up to October 2005 in a meta-analysis to give a comprehensive picture of the role of the three dopamine-related genes using multiple research methods and models. The DRD4 7-repeat (OR=1.34, 95% CI 1.23–1.45, P =2×10 ⁻¹² ) and 5-repeat (OR=1.68, 95% CI 1.17–2.41, P =0.005) alleles as well as the DRD5 148-bp allele (OR=1.34, 95% CI 1.21–1.49, P =8×10 ⁻⁸ ) confer increased risk of ADHD, whereas the DRD4 4-repeat (OR=0.90, 95% CI 0.84–0.97, P =0.004) and DRD5 136-bp (OR=0.57, 95% CI 0.34–0.96, P =0.022) alleles have protective effects. In contrast, we found no compelling evidence for association with the 480-bp allele of DAT (OR=1.04, 95% CI 0.98–1.11, P =0.20). No significant publication bias was detected in current studies. In conclusion, there is a statistically significant association between ADHD and dopamine system genes, especially DRD4 and DRD5 . These findings strongly implicate the involvement of brain dopamine systems in the pathogenesis of ADHD.

The large yellow croaker, Larimichthys crocea, is one of the most economically important marine fish species endemic to China. Its wild stocks have severely suffered from overfishing, and the aquacultured species are vulnerable to various marine pathogens. Here we report the creation of a draft genome of a wild large yellow croaker using a whole-genome sequencing strategy. We estimate the genome size to be 728 Mb with 19,362 protein-coding genes. Phylogenetic analysis shows that the stickleback is most closely related to the large yellow croaker. Rapidly evolving genes under positive selection are significantly enriched in pathways related to innate immunity. We also confirm the existence of several genes and identify the expansion of gene families that are important for innate immunity. Our results may reflect a well-developed innate immune system in the large yellow croaker, which could aid in the development of wild resource preservation and mariculture strategies.