What is UGT1A4?
The UGT1A4 gene encodes an enzyme of the glucuronidation pathway, a phase II metabolism process that transforms small lipophilic molecules into water-soluble excretable metabolites. The UGT1A4 enzyme mediates the metabolism of important psychotropic medications, including some tricyclic antidepressants, antipsychotics, and mood stabilizers1–20. Therefore, genetic polymorphisms in this gene may have pharmacological importance.
More than 100 UGT1A4 polymorphisms have been identified. Two of the best studied polymorphisms are UGT1A4*2, which results in a proline to threonine amino acid change at codon 24 (P24T) caused by a single C>A substitution, and UGT1A4*3, which results in a leucine to valine amino acid change at codon 48 (L48V) caused by a single T>G substitution21. Both of these variants are located in the first exon of the UGT1A4 gene and may result in altered enzyme activity, with UGT1A4*3 increasing glucuronidation and UGT1A4*2 decreasing glucuronidation.
Is there a connection between UGT1A4*3 rapid metabolism and the efficacy of psychotropic medications?
The UGT1A4*3 variant has been shown to have an effect on the metabolism of lamotrigine. Three in vivo studies (n=413) investigated the effect of UGT1A4*3 on lamotrigine metabolism and demonstrated that carriers of the G allele (TG + GG) had significantly reduced lamotrigine concentrations compared to wild-type (TT)3,22,23. One of these studies specifically examined the effect of genotype on lamotrigine efficacy by comparing seizure frequency before and after lamotrigine therapy. This study found that wild-type (TT) subjects exhibited significantly better therapeutic efficacy compared to carriers of the G allele22. While a fourth in vivo study (n=75) failed to find an association between UGT1A4*3 and lamotrigine clearance, the authors acknowledge several limitations to the study, which may cause this finding to be a false null association24. Contrary to the in vivo results, one in vitro study reported a decrease in the rate of lamotrigine glucuronidation in cells expressing the UGT1A4*3 variant. However, the authors give potential explanations for these contradictory findings, such as differences in experimental design and stability of enzyme preparations25.
The UGT1A4*3 variant has also been shown to affect the metabolism of olanzapine. Two in vitro studies investigated the effect of UGT1A4*3 on olanzapine metabolism and found that UGT1A4*3 causes increased enzyme activity9,26. Multivariate analyses indicated that Caucasian subjects (n=129) who were either heterozygous or homozygous for the UGT1A4*3 allelic variant exhibited a significant increase in olanzapine glucuronidation over patients with homozygous wild type genotypes (38% and 246% higher in *1/*3 and *3/*3 patients, respectively). Although serum concentrations of the parent drug were not affected by UGT1A4 genotype in this study, an increase in the glucuronidation rate supports the ultrarapid phenotype of this polymorphism26. Additionally, three in vivo studies (n=247) showed clear trends towards lower olanzapine concentrations in *3 allele carriers27–29. While another in vivo study (n=47) found a trend towards higher olanzapine concentrations in UGT1A4*3 carriers30, it has been shown that this contradictory finding may be attributed to erroneous genotyping methods 29.
Is there a connection between UGT1A4*2 reduced metabolism and the efficacy of psychotropic medications?
The overall literature on UGT1A4*2 is quite limited. Olanzapine, clozapine, and lamotrigine have been individually evaluated in three separate in vitro studies, each examining the effect of UGT1A4*2 on metabolism. All three studies found that UGT1A4*2 may cause lower enzyme activity9,20,25. However, three in vivo studies (n=415) examined the effect of UGT1A4*2 on lamotrigine metabolism, and found that the variant allele frequency was either too low to determine the effect of this polymorphism or the results were not significant3,22,23.
Conclusions
Multiple clinical studies have found UGT1A4*3 to be associated with higher enzyme activity3,22,23,26–29. This could result in clinically relevant reductions in exposure of drugs for which UGT1A4 is the major elimination route. Furthermore, it has also been shown that carriers of the UGT1A4*3 variant exhibited reduced therapeutic efficacy22. Thus, higher than average doses of UGT1A4 substrates may be required for patients carrying the UGT1A4*3 variant.
Due to the lack of in vivo evidence, more data is needed before UGT1A4*2 can be recommended for use in treatment selection.
Reference
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