Abstract
Uridine glucuronosyltransferase (UGT) gene polymorphisms have been linked to irinotecan toxicity. Our purpose was to study the association between UGT1A1*28, UGT1A7*2, and UGT1A7*3 polymorphisms and irinotecan toxicity in Greek patients receiving low-dose weekly irinotecan. Blood samples were collected for 46 patients. DNA was extracted and UGT1A1 promoter and UGT1A7 exon 1 genotyping was carried out. Laboratory tests and physical examination were performed on regular basis for the assessment of toxicity. UGT1A1*28 was significantly correlated with both haematologic and non-haematologic toxicity. Moreover, patients carrying UGT1A7 polymorphisms had significant incidence of toxicity. To conclude, UGT polymorphisms play a role in the toxicity of irinotecan, even if the drug is administered in low doses. The genotyping test may be a useful tool for the management of patients who are going to receive irinotecan.
Highlights
Pharmacogenomics studies the interaction between the genome and drugs on their way through the human body
Irinotecan is metabolised by carboxylesterases to form its active metabolite, SN-38
UGT1A1*28 polymorphism is about a TA insertion in the TATA box of the promoter of the gene, (TA)7 instead of (TA)6 UGT1A1*1
Summary
Pharmacogenomics studies the interaction between the genome and drugs on their way through the human body. Irinotecan is metabolised by carboxylesterases to form its active metabolite, SN-38 This is further glucuronated in the liver by glucuronosyltransferases and it forms the inactive metabolite SN-38G, which is eliminated mainly via the bile into the intestine. 10% of Caucasians are homozygous UGT1A1*28/UGT1A1*28 [(TA)7/(TA)7] for this polymorphism which leads to Gilbert’s syndrome These patients cannot glucuronate indirect to direct bilirubin sufficiently and may present with mild indirect hyperbilirubinemia. These patients, for the same reason, have a reduced glucuronidation of SN-38, and a higher exposure to the active metabolite. Polymorphisms of the gene encoding the extra hepatic glucuronosyltransferase UGT1A7, such as UGT1A7*2 and UGT1A7*3, may lead to elevated toxicity due to reduced reglucuronidation of SN-38 in the intestine [5, 6]. Eighty-seven per cent of Caucasians carry at least one of the UGT1A7*2, UGT1A7*3, and UGT1A7*4 polymorphisms, the last being rather rare [7]
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