Roles of UGT1A7 1A9 and 1A10 for Irnotecan Pharmacogenetics

UGT1A7, 1A9, and 1A10, which are expressed in the gastrointestinal tract, are assumed to more or less contribute to irinotecan PK/PD. The common polymorphism 1A9*1b(*22) [-118(T)10] was shown to enhance in vitro transcription (33). However, a correlation between 1A9*1b(*22) and hepatic 1A9 protein levels was not observed (51), and association of 1A9*1b(*22) with hepatic SN-38 glucuronidation was inconsistent between two studies (44, 45). Recently, the 1A9 3'-flanking SNP I399C>T has been associated with increased enzymatic activities of 1A1 and 1A9 in hepatic samples in Caucasians (45), but its clinical significance requires further evaluation. As for rare variations of 1A9 and 1A10, no significant effects of heterozygous 1A9*3 [98 T>C (M33T)] (52), 1A9*5 [766 G>A (D256N)] and 1A10*6(*3) [605C>T (T202I)] (46) were observed on the AUC ratio (SN-38 G/SN-38) or severe toxicities.

Regarding 1A7 polymorphisms, no associations of 1A7*2 and *3 with severe toxicities (grade 4 leukopenia or grade diarrhea) were observed in 118 Japanese patients who received irinotecan therapy, suggesting a minor role of 1A7 polymorphisms in SN-38G formation in vivo (53). The analysis of combinatorial haplotypes covering 1A9,1A7, and 1A1 in Japanese cancer patients has also suggested that the alterations in the AUC ratio (SN-38 G/SN-38) and the incidence of neutropenia were independent of the 1A9 or 1A7haplotypes (47).

On the other hand, unexpected effects of UGT1A7 and 1A9 polymorphisms on severe intestinal toxicity were reported in 66 colorectal cancer patients (including 55 Caucasians) who received capecitabine/irinotecan therapy (43). In this regimen, a major toxicity was grade 3 or 4 diarrhea (29%), while the incidences of grade 3 or 4 neutropenia (1%) and of co-occurrence of both severe toxicities (3%) were very low. Among the genetic polymorphisms of 1A1,1A6,1A7, and 1A9, a reduced incidence of severe diarrhea was observed in patients homozygous for low-activity 1A7 alleles (*2 and *3) which were linked to 1A9*1[-118(T)9], but not for the 1A1 or 1A6 polymorphisms. These findings suggest that it is the reduced UGT1A7/1A9 status that confers protection from severe diarrhea. The authors interpreted that the protection occurred through reduced SN-38 G excretion into the gut where SN-38 is regenerated from SN-38 G by bacterial (3-glucuronidase. This finding also raised a caution that higher intestinal levels of SN-38 G can promote diarrhea, while hepatic glucuronidation offers protection from neutropenia.

The recent pharmacogenetic studies with UGT1A haplotypes have collectively revealed the primary importance of UGT1A1 genotypes/haplotypes for prediction of severe toxicities and identified ethnic-specific genotypes (*28 for Caucasians, and *6 and/or *28 for Asians). Although there still remains a possible contribution of 1A9*1[-118(T)9]-1A7*3 to irinotecan pharmacogenetics, the close linkages of 1A9*1 [-118(T)9]-1A7* -1A1*28 and 1A9*1[-118(T)9]-1A7*3-1A1*6 make it difficult to distinguish a role of each genetic variation. However, regarding neutropenia, it is likely that severity of neutropenia depends on the activity of UGT1A1, which is a major UGT1A enzyme in the liver and plays a primary role in regulating the plasma level of SN-38. As for intestinal toxicity, it is possible that the genetic polymorphisms of 1A7 or 1A9, which are expressed in the gastrointestinal tract, affect the severity as reported in the capecitabine/irinotecan regimen.

There have been reports in which no significant (54) or only transient associations of *28 with severe hematologic toxicities were documented (55). Although these discrepancies may be partially due to the differences in the irinotecan regimens or population size, further confirmation of *28 genotyping benefits is needed.

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