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Guest Editorial Individual Differences in Toxicological Response Caused by a Diversity of Chemicals: Observations in Japan Introduction I send my congratulations to Chemical Research in Toxicology at the beginning of its new series, Toxicology: A Global Perspective. I would like to report on some toxicological issues (both societal and scientific) that are of importance in Japan. As described in this issue’s editorial, the field of toxicology in the United States is presented with numerous exciting research opportunities but faces challenges associated with fewer students, less available funding, etc. In Japan, it is my sense that similar alarming trends also apply to some extent, accompanied by a growing bipolarization between big national research projects and routine safety tests of new drug candidates in industrial laboratories. In terms of big projects, the first stage of the “Toxicogenomics Projects in Japan”, sponsored by national government funding, was conducted in 2002–2006. The National Institute of Health Sciences (NIHS) is a major organization within the Ministry of Health, Labour and Welfare (MHLW) of Japan. The MHLW Toxicogenomics Projects included NIHS and 17 Japanese pharmaceutical companies. They investigated gene expression in livers and kidneys of rats orally treated with 150 well-known typical toxicological chemicals by single or repeat exposure. Toxicological tests were also carried out in vitro using rat or human primary hepatocytes. The second stage of the project will be conducted in 2007–2011, mainly for further data analysis. On the basis of the results of this major effort, percellome toxicogenomics projects for predictive toxicology are ongoing (2003–) using quantitative PCR and DNA microarrys in mice (1). In contrast to the big national projects, extensive research on reactive metabolites and human-specific metabolites of investigational drugs is being conducted in many pharmaceutical laboratories corresponding to U.S. Food and Drug Administration guidelines. However, the results are generally not reported or open to the public in meetings and/or journals. The field of industrial toxicological research is a large black box, even with regard to high-technology methods. Recently, toxicologists in the industry, including drug metabolism and pharmacokinetic researchers, have been encouraged to talk with medicinal chemists and pharmacologists to develop unique medicines. The pharmaceutical companies need many young, active toxicologists to investigate the possible formation of reactive metabolites formed through metabolic clearance of potential drug candidates. This is one of the hottest topics in the evaluation of the pharmacological and toxicological potential of drug candidates by toxicologists.
Species Differences between Experimental Animals and Humans in the Metabolic Activation and Deactivation of a Variety of Chemicals Previous big projects were generally conducted using experimental animals such as rats and mice. Recently, it has
become possible to quantify substances with high sensitivity in human biological specimens, such as blood, urine, and breast milk. To overcome the species differences between drug-metabolizing enzymes, one of the recent proposals has been to derive screening levels for a wide range of chemicals in biological media (termed “human biomonitoring”). Research laboratories led by the U.S. Centers for Disease Control and Prevention (CDC) in its series, National Report on Human Exposure to Environmental Chemicals (CDC, 2005, NCEH Publication No. 05-0570), have dedicated substantial resources to designing and conducting human biomonitoring studies and compiling biomonitoring data for the general population. Biomonitoring efforts result in measured chemical concentrations in biological specimens (the result of absorption, distribution, metabolism, and excretion of administered doses) rather than estimated intake doses derived from animal studies. In Japan, The Japan Chemical Industry Association, in harmony with counterparts in the United States and the European Union, will establish a scientific task force team for advanced or improved risk assessment by using human biomonitering information. To put this approach into practice, the perspective of intra- and/or interspecies differences still needs to be addressed. There are many aspects to be considered such as the action of the chemicals in the body, especially their modes of metabolism, rates of metabolism and elimination, and retention.
Roles of Polymorphic Glutathione S-Transferases (GSTs) in Detoxification of Active Metabolites Formed though Oxidation With the advance of molecular toxicology, the roles of GSTs in detoxification of active metabolites derived from the oxidative metabolism of aflatoxin B1 (2), troglitazone (3), and carbamazepine (4) have been well-defined. Furthermore, the epidemiology of the contribution of the GSTs to hepatotoxicity associated with the use of these drugs is now becoming appreciated. Troglitazone is a good example of a drug that was marketed after approval by the U.S. Food and Drug Administration and MHLW of Japan but subsequently withdrawn as a result of idiosyncratic liver toxicity. Gene analyses of 25 patients suffering from troglitazone-induced liver injury in Japan demonstrated that 40% of the cases were associated with a null type of both GSTM1 and GSTT1 (3). It was suggested that the increased exposure to chemically reactive metabolites produced from troglitazone was the cause of the toxicity in these patients (3). These findings were supported by in vitro mechanistic studies, such as the cytochrome P450 3A4-catalyzed formation of a quinone epoxide metabolite from troglitazone (5). The formation of GSH conjugates of some of these reactive epoxides has also been reported (6, 7).
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The important roles of GST variants might well explain the toxicology of other types of chemicals in Japan. Recently, combined GSTM1 and GSTT1 null types have been reported as a risk factor for alcoholic mild liver dysfunction (8). These findings suggest that GST is likely to be widely involved in the detoxification of compounds that lead to chemicalmediated liver injury. Because the frequency of the null type of each above-mentioned GST form is 50% in Japan, the occurrence of the combination of the null types of both GSTM1 and GSTT1 is estimated to be 25%. Taken together, these variants may contribute to large interindividual differences in drug response after oxidative metabolism. In this context, further epidemiological approaches and molecular mechanistic studies must be carried out by many young toxicologists throughout the world, especially in Japan. Ethnic difference is clearly an important research topic in this field, as illustrated by the concentration of the genetic polymorphisms of GST isoforms reported here in the Japanese population.
Conclusions “Reactive metabolite studies” are still among the most important research topics for academic, industrial, and clinical toxicologists. It is not surprising that many drug regulatory authorities require evaluation of the formation and detoxification of reactive metabolites prior to market approval as well as during the postmarketing period. Both in vitro and in vivo studies have been conducted to develop and use medicines effectively. Epidemiological and mechanistic studies will further reveal the importance of genetic polymorphisms of GSTs to the toxicology of drugs and drug candidates. CRT is an excellent forum for reporting and discussing a variety of such toxicological studies, as it endeavors to bring some new energy to the field. The current Global Perspectives Forum offers a unique opportunity to draw attention to issues, such as GST polymorphisms, which have important implications for different societies around the world. On the basis of the current increasing trend for the mechanistic evaluation of reactive metabolites and their
potential for predictions for individual risk, these subjects should be hot topics challenging the toxicological community around the world. Hiroshi Yamazaki Laboratory of Drug Metabolism and Pharmacokinetics Showa Pharmaceutical UniVersity Machida, Tokyo 194-8543, Japan
References (1) Kanno, J., Aisaki, K., Igarashi, K., Nakatsu, N., Ono, A., Kodama, Y., and Nagao, T. (2006) “Per cell” normalization method for mRNA measurement by quantitative PCR and microarrays. BMC Genomics 7, 64. (2) Mcglynn, K. A., Rosvold, E. A., Lustbader, E. D., Hu, Y., Clapper, M. L., Zhou, T., Wild, C. P., Xia, X.-L., Baffoe-Bonnie, A., OforiAdjei, D., Chen, G.-C., London, W. T., Shen, F.-M., and Buetow, K. H. (1995) Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc. Natl. Acad. Sci. U.S.A. 92, 2384–2387. (3) Watanabe, I., Tomita, A., Shimizu, M., Sugawara, M., Yasumo, H., Koishi, R., Takahashi, T., Miyoshi, K., Nakamura, K., Izumi, T., Matsushita, Y., Furukawa, H., Haruyama, H., and Koga, T. (2003) A study to survey susceptible genetic factors responsible for troglitazoneassociated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 73, 435–455. (4) Ueda, K., Ishitsu, T., Seo, T., Ueda, N., Murata, T., Hori, M., and Nakagawa, K. (2007) Glutathione S-transferase M1 null genotype as a risk factor for carbamazepine-induced mild hepatotoxicity. Pharmacogenomics 8, 435–442. (5) Yamamoto, Y., Yamazaki, H., Ikeda, T., Watanabe, T., Iwabuchi, H., Nakajima, M., and Yokoi, T. (2002) Formation of a novel quinone epoxide metabolite of troglitazone with cytotoxicity to HepG2 cells. Drug Metab. Dispos. 30, 155–160. (6) Johnson, W. W., Yamazaki, H., Shimada, T., Ueng, Y.-F., and Guengerich, F. P. (1997) Aflatoxin B1 8,9-epoxide hydrolysis in the presence of rat and human epoxide hydrolase. Chem. Res. Toxicol. 10, 672–676. (7) Bu, H. Z., Kang, P., Deese, A. J., Zhao, P., and Pool, W. F. (2005) Human in vitro glutathionyl and protein adducts of carbamazepine10,11-epoxide, a stable and pharmacologically active metabolite of carbamazepine. Drug Metab. Dispos. 33, 1920–1924. (8) Oniki, K., Ueda, K., Hori, M., Mihara, S., Marubayashi, T., and Nakagawa, K. (2007) Glutathione-S-transferase (GST) M1 null genotype and combined GSTM1 and GSTT1 null genotypes as a risk factor for alcoholic mild liver dysfunction. Clin. Pharmacol. Ther. 81, 634–635.
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