Title:Idiosyncratic Drug Hepatotoxicity: Strategy for Prevention and Proposed Mechanism
Volume: 22
Issue: 4
Author(s): Toshihiko Ikeda
Affiliation:
关键词:
自身免疫反应，化学活性代谢物，共价结合蛋白质，细胞毒性T淋巴细胞，生物标记物，行或不行的决策，人体白细胞抗原，特殊毒性，非特异免疫反应，内在毒性，判断标准，风险估计
摘要: Idiosyncratic drug toxicity has led to the market withdrawal of many drugs in the past. Since animal
experiments are not predictive of such toxicity, the pharmaceutical industry continues to seek new
methodologies for the prevention of such effects. Although the mechanism of idiosyncratic drug toxicity remains
unclear, immune reactions are likely involved. Although drugs with low molecular weights are typically
not themselves immunogenic, these drugs may become haptens after being converted to chemically reactive
metabolites and becoming covalently cross-linked to proteins. Therefore, screening tests to detect chemically reactive
metabolites, most typically by trapping with glutathione, are carried out at early stages of drug development.
More quantitative methods are used in later stages of drug development; radioassays for covalent binding (using 14Cor
3H-labeled compounds) are most frequently employed. A zone classification system created by combining previous
assessment criteria for the chemically reactive metabolites in vitro (<50 pmole/mg-protein) and for the dose levels in
vivo (<10 mg/day) could be used for risk assessment of drug candidates. A mechanism for idiosyncratic, drug-induced
hepatotoxicity is proposed by analogy to virus-induced hepatitis, where cytotoxic T lymphocytes play an important
role; we suggest that idiosyncrasy reflects the involvement of polymorphisms in the human leucocyte antigen-encoding
loci. In fact, a strong correlation has been found between of idiosyncratic drug toxicity and specific human leucocyte
antigen genotypes. Therefore, screening of patients for gene biomarkers is expected to reduce the clinical risk of idiosyncratic
drug toxicity, thereby prolonging the life cycle of otherwise useful drugs.
