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- W4381489150 abstract "Aldo-keto reductase 1C3 (AKR1C3) plays a role in the detoxification and activation of clinical drugs by catalyzing reduction reactions. There are approximately 400 single nucleotide polymorphisms in the <i>AKR1C3</i> gene, but their impact on the enzyme activity is still unclear. This study aimed to clarify the effects of single nucleotide polymorphisms of <i>AKR1C3 </i>with more than 0.5% global minor allele frequency on the reductase activities for its typical substrates. Recombinant AKR1C3 wild-type and R66Q, E77G, C145Y, P180S, or R258C variants were constructed using insect Sf21 cells, and reductase activities for acetohexamide, doxorubicin, and loxoprofen by recombinant AKR1C3s were measured by LC‒MS/MS. Among the variants tested, the C145Y variant showed remarkably low (6-14% of wild-type) intrinsic clearances of reductase activities for all three drugs. Reductase activities of these three drugs were measured using 34 individual Japanese liver cytosols, revealing that heterozygotes of the SNP g.55101G>A tended to show lower reductase activities for three drugs than homozygotes of the wild-type. Furthermore, genotyping of the SNP g.55101G>A causing C145Y in 96 Caucasians, 166 African Americans, 192 Koreans, and 183 Japanese individuals was performed by polymerase chain reaction-restriction fragment length polymorphism. This allelic variant was specifically detected in Asians with allele frequencies of 6.8% and 3.6% in Koreans and Japanese, respectively.<b></b>To conclude, an <i>AKR1C3</i> allele with the SNP g.55101G>A causing C145Y would be one of the causal factors for interindividual variabilities in the efficacy and toxicity of drugs reduced by AKR1C3. <b>Significance Statement</b> This is the first study to clarify that the <i>AKR1C3 </i>allele with the SNP g.55101G>A causing C145Y results in a decrease in reductase activity. Since the allele was specifically observed in Asians, the allele would be a factor causing an interindividual variability in sensitivity of drug efficacy or toxicity of drugs reduced by AKR1C3 in Asians." @default.
- W4381489150 created "2023-06-22" @default.
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- W4381489150 date "2023-06-21" @default.
- W4381489150 modified "2023-10-18" @default.
- W4381489150 title "<b><i>In vitro</i>evaluation of the reductase activities of human<i>AKR1C3</i>allelic variants</b>" @default.
- W4381489150 doi "https://doi.org/10.1124/dmd.123.001264" @default.
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