Prevalence of the UGT1A1*6 (c.211G>A) Polymorphism and Prediction of Irinotecan Toxicity in Iranian Populations of Different Ethnicities

Abstract

Background: Pharmacogenetic studies on irinotecan treatment in patients with metastatic colorectal cancer have indicated that genetic polymorphisms in UGT1A1*6 can lead to decreased enzyme activity and accumulation of the toxic metabolite SN-38. Here, we compared the prevalence of UGT1A1*6 in an Iranian population of different ethnicities with those of other populations. Materials and Methods: A total of 300 healthy people of different ethnic groups including Persian, Azari, Lure, Kurdish, Arab, Baluch and Caspian in the Iranian population were enrolled. Genotyping of the UGT1A1*6 alleles (G/G, A/G, A/A) was performed by polymerase chain reaction-restriction fragment length polymorphism and direct genomic DNA sequencing. Result: The most predictive genotype among the Iranian ethnic groups, especially Persian, was the G/G genotype (wild-type genotype). The frequency of the A/G genotype among the Persian, Azari, Lure, Kurdish, Arab, Baluch and Caspian ethnicities were 15.69% (n = 27), 11.11% (n = 8), 5.88% (n = 1), 9.09% (n = 1), 10% (n = 1), 20% (n = 1) and 0% (n = 0), respectively. Only one person with Persian ethnicity was homozygous for the mutation in UGT1A1*6 (0.58%). Additionally, the frequency of the A and G alleles in Iranians was 6.83 and 93.16%, respectively. Conclusion: The identification of the UGT1A1*6 alleles is necessary among the different Iranian ethnic groups before irinotecan therapy, suggesting that genotyping would be helpful for clinicians to optimize chemotherapy or identify individuals at risk of adverse drug reactions before clinical trials.

Phase II and UGT1A1 Polymorphism Study of Two Different Irinotecan Dosages Combined with Cisplatin as First-Line Therapy for Advanced Gastric Cancer

“…UGT1A1*6, another polymorphism, has a higher defective allele frequency in Asians compared with Caucasians, and was related to a higher frequency of severe toxicities in patients receiving irinotecan [20,21]. On the other hand, previous investigation failed to find a significant correlation of UGT1A1*6 and irinotecan-induced neutropenia [22,23], which was consistent with the results in our present study.…”

Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III

“…Uridine 5′-diphospho (UDP)-glucuronosyltransferases (UGTs) are one of the most important phase II DMEs and have been reported to participate in the metabolism of many important clinical drugs. UGT1A1 is involved in the glucuronidation metabolism of first-line antitumour drug irinotecan (Shakibi et al, 2015). UGT1A9 catalyses the glucuronidation of propofol which is an important hypnotic/amnestic agent (Liang et al, 2011).…”

Inhibition of UDP-Glucuronosyltransferase (UGT) Isoforms by Arctiin and Arctigenin

“…UDP‐glucuronosyltransferases (UGTs) are important phase II drug‐metabolizing enzymes involved in the metabolism of many clinical drugs. For example, UGT1A1 is involved in the metabolic elimination of the first‐line anticolon cancer drug irinotecan (Shakibi et al , ). The metabolic elimination of propofol was mainly catalyzed by UGT1A9 (Mukai et al , ).…”