Biotechnology advances have provided novel methods for the risk assessment of chemicals. The application of microarray technologies to toxicology, known as toxicogenomics, is becoming an accepted approach for identifying chemicals with potential safety problems. Gene expression profiling is expected to identify the mechanisms that underlie the potential toxicity of chemicals. This technology has also been applied to identify biomarkers of toxicity to predict potential hazardous chemicals. Ultimately, toxicogenomics is expected to aid in risk assessment. The following discussion explores potential applications and features of the Japanese Toxicogenomics Project.

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Metabolic capacities for debrisoquin, sparteine, mephenytoin, nifedipine, and midazolam, which are substrates of polymorphic CYP2D6, CYP2C19, and CYP3A, have been reported to exhibit, in many cases, remarkable interindividual and ethnic differences. These ethnic differences are partly associated with genetic differences. In the case of the drug transporter ABCB1/MDR1, interindividual differences in its transporter activities toward various clinical drugs are also attributed to several ABCB1/MDR1 genetic polymorphisms. In this review, the existence and frequency of various low-activity alleles of drug metabolizing enzymes as well as populational drug metabolic capacities are compared among several different races or ethnicities. Distribution of nonsynonymous ABCB1/MDR1 SNPs and haplotype frequency in various races are summarized, with the association of nonsynonymous SNPs with large functional alterations as a rare event.

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ABSTRACT:Patients with chronic hepatitis C viral infection underwent liver biopsies and laboratory studies for evaluation and to determine subsequent treatment. Changes in status of drug metabolism and disposition may vary with chronic hepatitis C stage and should be assessed. Total RNA was extracted from liver biopsy specimens (n ‫؍‬ 63) and reverse transcribed to yield cDNA. Relative mRNA levels of drug-metabolizing enzymes, transporters, nuclear receptors, and proinflammatory cytokines were analyzed with normalization to glyceraldehyde 3-phosphate dehydrogenase expression. mRNAs encoding cytochromes P450 1A2, 2E1, and 3A4, and drug transporters, Na ؉ -taurocholate-cotransporting polypeptide, organic anion-transporting peptide-C, and organic cation transporter 1 showed remarkable decreases, and tumor necrosis factor-␣ showed an increase according to fibrosis stage progression. HepG2 cells and primary hepatocytes of two human individuals were treated with interleukin 1␤, interleukin 6, or tumor necrosis factor-␣. CYP1A2 and Na ؉ -taurocholate-cotransporting polypeptide mRNA levels significantly decreased in HepG2 cells with interleukin 1␤ and interleukin 6 treatments. CYP2E1 and organic cation transporter 1 mRNA levels significantly decreased with tumor necrosis factor-␣ treatment only in HepG2. These results suggested that down-regulation of CYP1A2, 2E1, and 3A4, and drug transporters, Na ؉ -taurocholate-cotransporting polypeptide, organic anion-transporting peptide-C, and organic cation transporter 1, manifested in livers of patients with chronic hepatitis C viral infection, was associated, at least in part, with the elevated production of proinflammatory cytokines, including tumor necrosis factor-␣.Infection and inflammation generally cause a decrease in hepatic capacity for drug metabolism and disposition. Using lipopolysaccharide models of hepatic inflammation, a number of investigators have demonstrated decreases in the expression of various drug-metabolizing enzymes (Iber et al., 1999;Renton, 2004). Bacterial and viral infections are associated with the induction of various cytokines, including interleukins (ILs) 1␤ and 6, tumor necrosis factor (TNF)-␣, and interferon-␥, which decrease the level of hepatic drug-metabolizing enzymes (Iber et al., 1999;Renton, 2004). Hepatitis C virus (HCV) infection was reported to cause changes in levels of drugmetabolizing enzymes cytochrome P450 2E1 (Gochee et al., 2003), an oxidative stress-related enzyme, and glutathione peroxidase (Levent et al., 2006); and nuclear receptors, including peroxisome proliferator-

Oxidative stress is the main cause of neuronal damage in traumatic brain injury, hypoxia/reperfusion injury, and neurodegenerative disorders. Although extracellular nucleosides, especially adenosine, are well known to protect against neuronal damage in such pathological conditions, the effects of these nucleosides or nucleotides on glial cell damage remain largely unknown. We report that ATP but not adenosine protects against the cell death of cultured astrocytes induced by hydrogen peroxide (H2O2). ATP ameliorated the H2O2-induced decrease in cell viability of astrocytes in an incubation time- and concentration-dependent fashion. Protection by ATP was inhibited by P2 receptor antagonists and was mimicked by P2Y1 receptor agonists but not by adenosine. The expressions of P2Y1 mRNAs and functional P2Y1 receptors in astrocytes were confirmed. Thus, ATP, acting on P2Y1 receptors in astrocytes, showed a protective action against H2O2. The astrocytic protection by the P2Y1 receptor agonist 2-methylthio-ADP was inhibited by an intracellular Ca2+ chelator and a blocker of phospholipase C, indicating the involvement of intracellular signals mediated by Gq/11-coupled P2Y1 receptors. The ATP-induced protection was inhibited by cycloheximide, a protein synthesis inhibitor, and it took more than 12 h for the onset of the protective action. In the DNA microarray analysis, ATP induced a dramatic upregulation of various oxidoreductase genes. Taken together, ATP acts on P2Y1 receptors coupled to Gq/11, resulting in the upregulation of oxidoreductase genes, leading to the protection of astrocytes against H2O2.

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