Gly143Glu polymorphism of the human carboxylesterase1 gene in an Asian population.

Dear Editor, As Drs Zhu and Markowitz commented in their letter, it is widely recognized that carboxylesterase (CES) is an important enzyme that activates prodrugs in vivo. In our report, the interindividual variability observed in the metabolism of oseltamivir could not be explained on the basis of the CES1A1 genotypes and the number of CES1 functional genes [1]. However, the area under the curve (AUC) for oseltamivir for one subject in our study was approximately 10-fold higher than the corresponding AUCs for the rest of the subjects. A previous report has shown that two CES1 variants, Gly143Glu (rs71647871) and Asp260fs (rs7164782), reduce the hydrolytic activity of CES1 [2]. Moreover, the Gly143Glu variant has been shown to be associated with impaired oseltamivir metabolism [3, 4]. Although we are very interested in these polymorphisms, the Gly143Glu polymorphism appears to be extremely rare in the Asian population, as indicated by Zhu and Markowitz [2, 5], and the Asp260fs polymorphism is even rarer [2]. Gly143Glu is located in CES1A1 rather than CES1A2/CES1A3 [5], whereas Asp260fs is a mutation in the CES1A2 gene [5]. The transcriptional efficiency of CES1A1 is markedly higher than that of CES1A2. Therefore, the Gly143Glu mutation may be more important in CES1 metabolism. After submitting the manuscript, we examined the frequency of the Gly143Glu and Asp260fs polymorphisms in nearly 400 Japanese subjects. As expected, no such Glu variants were found in the DNA of the subjects, including those who participated in the reported study [1]. In addition, no Asp260fs variants were observed in our samples. Therefore, another hitherto unknown mutation in the CES1 gene may be involved in the slow oseltamivir metabolism in the poor metabolizer identified in our study. Additional studies are required to further elucidate the cause of the individual differences observed in CES1 substrate drug metabolism.