[Interindividual differences in efficacy and toxicity induced by therapeutic drugs and xenobiotics in relation to genetic polymorphisms in xenobiotic metabolizing enzymes].

Humans incessantly ingest wide-variety of chemicals through the administration of therapeutic drugs, diets and beverages. Humans are also exposed to environmental mutagens and carcinogens and substances causing endocrine disruption. Metabolism and disposition have been regarded as one of the most important determinants of efficacy and toxicity induced by ingested chemicals, since remarkable individual difference was observed in the plasma concentration and/or urinary excretion after the administration of wide variety of therapeutic drugs such as isoniazid, sulfamethazine, debrisoquin, sparteine, mephenytoin and so on. This variability is resulted from pharmacogenetically regulated difference in the activities of xenobiotic metabolizing enzymes (so called genetic polymorphisms). Polymorphic appearance of xenobiotic metabolism has also been observed with various toxic substances such as ethanol, acetaldehyde, benzene, organic phosphates and environmental mutagens and carcinogens. Enzymes which show genetic polymorphisms include cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, CYP2C19, CYP2D6 and CYP2E1) and phase II drug metabolizing enzymes (arylamine N-acetyltransferases, glutathione S-transferases and UDP-glucuronosyl transferases). A number of mutations on the genes encoding polymorphic xenobiotic metabolizing enzymes have been associated with the remarkable individual difference in the metabolism and disposition in vivo. Individuals with distinct alleles of genes which encode defective enzymes have been shown to be at higher risk to toxic side effects by therapeutic drugs and more susceptible to certain malignant diseases. Research has to be conducted for each human race concerning risk assessment of chemicals, since ethnic differences in frequency of distinct alleles of genes encoding xenobiotic metabolizing enzymes are reported. In case of type 1 Crigler-Najjar syndrome causing unconjugated hyperbilirubinemia, complete loss of bilirubin-detoxifing UDP-glucuronosyl transferase has been attributed to nonsense, missense, and/or frameshift mutations that occurred at various sites on UGT1 gene. Thus, genetic polymorphisms of xenobiotic metabolizing enzymes are one of the most important factors influencing efficacy of therapeutic drugs and toxicity by wide-variety of chemicals.