Role of UGT1A1*28 and UGT1A1*6 for irinotecan-induced adverse drug reaction

Irinotecan is widely used in the treatment of colorectal, gastric, and lung cancers. However, adverse drug reactions such as severe diarrhea and neutropenia limit the dose of this drug. Irinotecan is metabolized by carboxylesterase to form an active metabolite, 7-ethyl-10-hydroxycamptothecin(SN-38), which in turn is subsequently conjugated by UGT-glucuronosyltransferase 1A1(UGT1A1)to yield an inactive form, SN-38 glucuronide(SN-38 G). The UGT1A1 gene polymorphisms contribute to the individual variation in adverse events among patients administered irinotecan. However, the distribution of polymorphisms shows large interethnic differences. The distribution of UGT1A1*28 greatly differs between Caucasians and Japanese; the frequency of UGT1A1*28 is high in Caucasians, whereas it is low in Asians including Japanese. Recently, it has been demonstrated that genetic variants of UGT1A1*6 in addition to UGT1A1*28 are associated with the occurrence of adverse events in irinotecan chemotherapy in Asians. This review summarizes recent studies to outline the role of UGT1A1*28 and UGT1A1*6 for irinotecan-induced adverse drug reaction in Japanese cancer patients.