Influence of AS3MT polymorphisms on arsenic metabolism and liver injury in APL patients treated with arsenic trioxide

Highlights: • AS3MT rs11191453 genotypes were associated with arsenic metabolism. • AS3MT rs10748835 genotypes were associated with arsenic metabolism and liver injury. • For the two SNPs, additive effects exist on arsenic metabolism and liver injury. • AS3MT SNPs, a novel predictive biomarker in APL patients treated with As₂O₃. -- Abstract: Arsenic-induced side effects limit its application in the treatment of acute promyelocytic leukemia (APL). We recently demonstrated that AS3MT 14215 (rs3740390) genotypes were associated with urinary arsenic metabolites and hematological and biochemical values. To further decipher the role of AS3MT genotypes on arsenic metabolism and toxicity, AS3MT 27215 (rs11191446), 35587 (rs11191453), 35991 (rs10748835), and their interactive effects were examined in fifty APL patients treated with arsenic trioxide (As₂O₃) for the first time. Urinary arsenic metabolites and methylation capacity indexes were evaluated by the percentage of inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), primary methylation index (PMI, MMA/iAs), secondary methylation index (SMI, DMA/MMA), and total methylation index (TMI, [MMA+DMA]/iAs). Results showed 27215 (rs11191446) genotypes had no statistical significance in arsenic metabolism, as only 5 (10%) patients were the non-wild-type genotypes. 35587 (rs11191453) genotypes were significantly associated with MMA%, DMA%, and SMI. 35991 (rs10748835) genotypes were significantly associated with iAs%, DMA%, PMI, TMI, and the level of ALT and AST. Patients with both 35587 (rs11191453) TT and 35991 (rs10748835) AG+GG genotypes were significantly associated with DMA% and SMI. In addition, patients with both 35991 (rs10748835) AA and 35587 (rs11191453) TC+CC genotypes had the highest DMA%, SMI, and TMI, but the lowest iAs%, ALT and AST level, indicating that additive effects exist on arsenic metabolism and liver function. Our data promotes the realization that AS3MT 35587 (rs11191453), 35991 (rs10748835), especially their joint genotypes 35991 (rs10748835) AA / 35587 (rs11191453) TC+CC, is a novel predictive biomarker for the therapeutic efficacy of As₂O₃ in the treatment of APL.