Key result
Ten SULT1C4 allozymes demonstrate altered doxorubicin-sulfating activity versus the wild-type enzyme.
Why the study?
SULT1C4 is critical to doxorubicin metabolism, but the functional impact of SULT1C4 single nucleotide polymorphisms on doxorubicin sulfation was unclear.
Genetic polymorphisms in SULT1C4 lead to differential doxorubicin sulfation, suggesting that individual genotypes may influence doxorubicin metabolism.
SULT1C4 variants may alter doxorubicin sulfation; hypothesis-generating for pharmacogenomic dosing studies.
Doxorubicin is a chemotherapeutic drug widely utilized in cancer treatment. An enzyme critical to doxorubicin metabolism is the cytosolic sulfotransferase (SULT) SULT1C4. This study investigated the functional impact of SULT1C4 single nucleotide polymorphisms (SNPs) on the sulfation of doxorubicin by SULT1C4 allozymes. A comprehensive database search was performed to identify various SULT1C4 SNPs. Ten nonsynonymous SULT1C4 SNPs were selected, and the corresponding cDNAs, packaged in pGEX-2TK expression vector, were generated via site-directed mutagenesis. Respective SULT1C4 allozymes were bacterially expressed and purified by affinity chromatography. Purified SULT1C4 allozymes, in comparison with the wild-type enzyme, were analysed for sulphating activities towards doxorubicin and 4-nitrophenol, a prototype substrate. Results obtained showed clearly differential doxorubicin-sulphating activity of SULT1C4 allozymes, implying differential metabolism of doxorubicin through sulfation in individuals with distinct SULT1C4 genotypes.
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Gohal et al. (2021) studied this question. SULT1C4 single nucleotide polymorphisms (allozymes) vs. Wild-type SULT1C4 enzyme was evaluated on Sulfating activity towards doxorubicin. Ten nonsynonymous SULT1C4 allozymes exhibited significantly differential doxorubicin-sulfating activities compared to the wild-type enzyme, with five showing no detectable activity and three showing increased activity.
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