Received for publication February 21, 2006.
Revised March 24, 2006.
Accepted for publication March 29, 2006.

The novel UGT1A9 intronic polymorphism I399 appears as a predictor of SN-38 glucuronidation levels in liver microsomes

Abstract

Polymorphisms in UGT1A9 are associated with reduced toxicity and increased response to irinotecan in cancer patients. To clarify the role of UGT1A9 variants in the glucuronidation of SN-38, UGT protein expression, glucuronidation activities for SN-38 and probe substrates of the UGT1A9 and UGT1A1 were measured in 48 human livers. Genotypes were assessed for UGT1A9 (-2152C>T, -275T>A, -118T_9>10), three novel UGT1A9 variants (-5366G>T, -4549T>C and I399C>T) and UGT1A1 (-53TA_6>7, -3156G>A and -3279T>G). Of all variants, the UGT1A9 I399C>T was associated with the most dramatic change in SN-38G (2.64-fold; p=0.0007). Compared to UGT1A9 I399C/C, homozygous I399T/T was associated with elevated UGT1A1 and UGT1A9 proteins and higher glucuronidation of probe substrates (p<0.05). The very low LD (r²<0.19) between UGT1A9 I399 and all other UGT1A1 and UGT1A9 variants suggests either a direct effect or linkage to unknown functional variant(s) relevant to SN-38 glucuronidation. The UGT1A9-118T_9/10 was also linked to alteration of SN-38 glucuronidation profiles in the liver (p<0.05) and associated with higher UGT1A1 protein (p=0.03). However, UGT1A9-118T₁₀ appears to have low functional impact due to the lack of correlation with UGT1A9 protein levels and a modest 40% higher reporter gene expression associated with the -118T₁₀ allele in HepG2 cells (p=0.004). In contrast, the UGT1A9 -5366T, -4549C, -2152T and -275A, associated with higher UGT1A9 protein (2-fold; p<0.05), have no influence on SN-38G. Despite some limitation in sample size, our results indicate that UGT1A9 I399 and -118T_9/10 may represent additional candidates in combination with UGT1A1 promoter haplotypes for the prediction of SN-38 glucuronidation profile in vivo.

Key words: anticancer agents, drug disposition, genetic polymorphism, glucuronidation, pharmacogenetics, UDP glucuronyltransferases

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