and for carriers of the SLC47A1 A allele (44%, rs2289669) as compared with G/G wild‐type genotype (12.5%). Patients who were carriers of at least one A allele for SLC22A1 (41.9%) versus C/C genotype exhibited increased metformin levels. The authors concluded that polymorphisms in drug transporters may be viable biomarkers to predict progression and toxicity to metformin in clinical studies for castration‐resistant prostate cancer.
3.7.3 Cisplatin Toxicity
Cisplatin is a cancer therapeutic known to cause ototoxicity and nephrotoxicity in patients. A study in Canada enrolled patients (n = 206; predominantly Caucasian) receiving cisplatin and radiation for locally advanced head and neck squamous cell carcinoma and prospectively assessed for ototoxicity (defined as grade 2 or above from baseline, CTCAE v4.02) [124]. Pharmacogenetics of various transporters, including SLC47A1/MATE1, were assessed as covariates. Protective factors for ototoxicity risk were weekly vs. high‐dose cisplatin and SLC47A1/MATE1 (rs2289669) A/A carriers. Survival outcomes were not found to be statistically or clinically impacted by genetic variation in SLC47A1. A study in Chinese non‐small‐cell lung cancer patients (n = 403) also evaluated transporter genotype and toxicity response to platinum chemotherapy (83% cisplatin, 17% carboplatin) [125]. The SLC22A2 variant (rs316019; 808 G > T) was associated with hepatotoxicity and hematological toxicity. By comparison, SLC47A1 (rs2289669) was associated with hematological toxicity. Notably, the study did not appear to assess for renal toxicities secondary to platinum compounds.
While serum creatinine has been a traditional biomarker for kidney injury, limitations have garnered interest in urinary proteins that are secreted from anatomic locations in the nephron and can represent sites of injury to drugs and toxins. A recent study evaluated pharmacogenetics of transport pathways in cisplatin‐treated patients (n = 57) and traditional and novel biomarkers of acute kidney injury [99]. Notably, increases in urinary biomarkers were associated with polymorphisms in SLC22A2 and SLC47A1. The SLC47A1 variant (rs2289669) was significantly associated with an increase in the urinary biomarkers KIM‐1 (3.6‐fold) and MCP‐1 (2.9‐fold). In this publication, the decreased function of SLC47A1 associated with elevations in some urinary biomarkers in patients prescribed cisplatin. The results suggest that several transport polymorphisms (and phenotypes) may be implicated in cisplatin nephrotoxicity.
3.7.4 Flutamide Liver Injury
The mRNA level of SLC47A1 in human peripheral blood cells was previously found to be reflective of liver and kidney expression and predictive for drug‐induced liver injury to flutamide treatment for prostate cancer [126]. In the study, blood samples were obtained from Japanese patients (n = 52) prior to treatment and follow‐up of liver function enzymes (AST and ALT) was obtained for 6 months. Out of the 17 patients with elevations in liver enzymes, 15 had a >2‐fold decrease in SLC47A1 expression. The authors also conducted an experiment in Mate1 knockout mice showing elevated serum concentrations of a flutamide metabolite (4‐nitro‐3‐(trifluoromethyl)phenylamine). It was not reported whether the metabolite is a MATE1 substrate. The results suggest an association between MATE1 mRNA expression in blood and liver toxicity due to flutamide. A subsequent study in Japanese patients (n = 22) with prostate cancer evaluated SLC47A1 polymorphisms (rs2252281 and rs2453579) to determine whether mRNA expression in peripheral blood was associated with SLC47A1 genetics [127]. MATE1 mRNA levels were significantly greater in patients who were heterozygous for the rs2453579 and rs2252281 haplotype, suggesting the potential of a biomarker for predicting risk of liver injury secondary to flutamide. It is unclear, however, why the homozygous wild‐type and variant haplotypes both exhibited reduced expression, limiting the application of the results without further validation. Higher MATE1 expression in blood may be associated with organ levels and can be monitored for risk of flutamide toxicities.
3.8 CONCLUSIONS
MATE transporters have emerged as a novel and exciting route for the excretion of drugs, toxicants, and endogenous molecules. Full characterization of MATE transporters using contemporary structural biology approaches will aid in elucidating understanding of their molecular and biochemical activity. Likewise, further adaptation of MATE substrates in drug–drug interaction and pharmacogenetic studies will greatly advance the translatability of fundamental knowledge regarding this transporter family.
ACKNOWLEDGMENT
This work was supported, in part, by the National Institute of General Medical Sciences [Grant GM123330] and the National Institute of Environmental Health Sciences [Grants ES005022, ES020721].
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