An overview of the comparative toxicogenomics database

Toxicogenomics is a relatively new field of study oriented toward the investigation of the interplay between environmental factors and specific genes and genetic haplotypes, and more specifically how these interactions relate to the etiology of chronic disease. In their Perspective article, Mattingly et al (pp xx–xx) describe the Comparative Toxicogenomics Database, which is to be the first publicly available, curated database devoted to information regarding human genes and proteins of toxicological significance. This database will also serve as a clearinghouse for comparative toxicogenomic data, integrating the relevant information collected from a variety of well-characterized model species.

Protecting communities in pharmacogenetic and pharmacogenomic research

A major component of pharmacogenetic and pharmacogenomic studies is the identification of common genetic differences among different communities and ethnic groups. As important as such studies are, they also have the potential to raise considerable ethical issues, as they are inevitably involved with the controversial science (and politics) of studying racial differences. Weijer and Miller (pp xx–xx) analyze the issues relating to the protection of communities involved in such research, and suggest a policy framework for resolving some of these quandaries.

Multilocus effects of the RAA system genes

Hypertension is recognized as a major risk factor for cardiovascular disease, stroke and renal disease. Pharmacological treatments exist, and thiazide diuretics are the most commonly prescribed class of drugs for hypertension, although there is significant variation in patient responsiveness to such treatment. Since these drugs target gene products from the renin angiotensin aldosterone (RAA) system, which regulates blood pressure levels and fluid electrolyte balance, Frazier et al (pp xx–xx) have investigated the impact of sequence variation in five RAA genes on the efficacy of thiazide diuretic treatment.

Carcinogenesis by furazolidone and metabolites in mollies

Furazolidone (FZD) is an antibacterial drug that is widely used for disease prevention in livestock, but whose use has long been banned in the USA due to possible carcinogenic properties. However, human consumers are generally not exposed to FZD directly, but rather to its metabolites, which include the compounds AOZ and FOZ. Auro et al (pp xx–xx) exposed two species of fish to FZD, and then to the compounds that were produced following metabolism of FZD by cytochrome p450, which include both AOZ and FOZ. Their findings indicate that, although FZD is clearly carcinogenic, its byproducts seem to pose no significant risk in this model.

Association between the GNB3 gene and depression

G protein signaling is involved in a diverse array of pathways, including the transduction of signals from a variety of neurotransmitters. A recent study has linked a polymorphism in the â3 subunit of G protein with depression, indicating that the C825T allele of this gene appears significantly more often in depressive patients. In this article, Lee et al (pp xx–xx) examine a Korean sample of 106 patients suffering from major depressive disorders (MDD) and 133 control patients, in an effort to better characterize the relationship between this polymorphism and the clinical symptoms of MDD.

CYP3A5 polymorphism and nifedipine pharmacokinetics

Cytochrome P450 3A (CYP3A) is abundantly expressed in the liver and small intestine, and is estimated to contribute to the metabolism of 50% of all prescription drugs. A number of polymorphisms have been identified recently in CYP3A that can trigger frameshifts or alternative splicing, and as such are believed to have a significant impact on CYP3A's metabolic efficiency. Fukuda et al (pp xx–xx) examine the influence of CYP3A5^*3, a polymorphism previously characterized as relatively common among Japanese, on the disposition of nifedipine.

Warfarin sensitivity related toCYP2C9, CYP3A5, ABCB1 (MDR1)

Warfarin is an anticoagulant commonly prescribed for the treatment of stroke and pulmonary embolism, among other conditions. There are significant interindividual variations in the response to warfarin treatment, sometimes resulting in serious complications. A number of cytochromes are involved in the metabolism of warfarin, depending upon which enantiomeric form is involved, and some evidence also suggests a role for P-glycoprotein (the ABCB1 gene product) in warfarin disposition. Wadelius et al (pp xx–xx) compare the impact of warfarin treatment against genetic variation of key metabolic genes in order to identify key pharmacogenetic factors for treatment efficacy.

Genetic susceptibility to tranilast-induced hyperbilirubinemia

Tranilast is an antiallergic drug currently under investigation for use in patients undergoing treatment of ischemic heart disease. During the phase III trial, approximately 12% of the patients exhibited hyperbilirubinemia, raising concerns about the hepatotoxicity of tranilast. Gilbert's syndrome is a heritable form of benign hyperbilirubinemia that has been linked to variations in the UGT1A1 gene; Danoff et al (pp xx–xx) investigated the extent to which these variations were related to hyperbilirubinemia in recipients of tranilast, and found that genetic predisposition to Gilbert's syndrome may be an accurate predictor.

Novel human SULT gene identification

The SULT superfamily of enzymes is involved in catalyzing the conjugation of sulfate for the biotransformation of a wide range of compounds. A total of 10 SULT genes have been identified to date in humans. Freimuth et al (pp xx–xx) undertook a hunt for novel SULT genes, using a variety of search methodologies to scan publicly available human genome data; the results from their investigation reveal seven novel SULT genes, and provide some potential insights into the evolution of this gene family in humans.

MTHFR and MTHFD1 polymorphisms and childhood ALL outcome

MTHFR and MTHFD1 are essential enzymes in the process of folate metabolism, and as such can potentially play an important role in determining susceptibility to a variety of diseases, or even impact a patient's response to compounds used for chemotherapy. One such chemotherapeutic agent is methotrexate, used to treat childhood acute lymphoblastic leukemia (ALL), and Krajinovic et al (pp xx–xx) examine here the possible impact of MTHFR and MTHFD1 polymorphisms on outcome from the treatment of ALL with methotrexate.