Organic anion transporters

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Revision as of 13:59, 24 November 2023

Introduction

History

Function

Structure

The OAT family are transmembrane proteins of about 550 amino acids with intracellular N- and C-terminal and 12 α-helical transmembrane domains (TMDs). The transporter has 2 large loops: an extracellular one between TMD1/2 and an intracellular one between TMD6/7^[1].

Three highly conserved regions allow for substrate specificity and the activity of the transporter in this protein: the first is the loop between TMD1/2, which mediates homo-oligomerization^[2] and contains several glycosylation sites; the second is the intracellular loop between TMD6/7, which has phosphorylation sites and is involved in transcriptional regulation^[2]; and the third is domains 9 and 10^[1].

Mechanism of action

Inhibitors and activators

Alterations of the function

The pharmacokinetics and disposal of drugs may be significantly impacted by modifications in the activity of OATs, which can arise from a variety of causes.

Genetic polymorphisms^[3]

Examining the pharmacological effects of naturally occurring mutations in OATs is essential because they may explain different responses to drug treatment. As of right now, investigation has been conducted only into the genetic polymorphisms of OAT1-4.

• OAT1: numerous SNPs, both intronic and exonic, have been found in individuals representing the main ethno-geographical divisions. Among the results, we can observe cases, such as the R50H variant, where there is an increased uptake of acyclic nucleoside phosphonates, but no changes in the transport of para-aminohippurate (PAH) (used as a control in the study of these transporters) are identified; other variants, like K525I, P104L, or R293W, exhibit no change in function; lastly, certain variants, like R454Q, do not exhibit any uptake of PAH, but show normal renal clearance of acyclic nucleoside phosphonates.

• OAT2: compared to the other three transporters, OAT2 has far fewer SNPs, these being common among individuals of different ethnic groups. However, no major change in function has been identified in any of them.

• OAT3: the polymorphisms in this transporter that have been investigated primarily indicate changes in the transport of cimetidine and estrone-3-sulfate (ES), with some variants (like R149S or G239X) showing no uptake at all, and others (like R277W) solely showing reduced ES uptake. Nonetheless, the majority of the detected SNPs do not exhibit a change in function.

• OAT4: this transporter's polymorphisms are the most researched. Important variants include the E278K, which has decreased uptake of ES, Dehydroepiandrosterone sulfate, and ochratoxin A (OTA) due to a decrease in maximum transporting rate and transporter-substrate affinity; the L29P, R48X, and H469R variants, which have decreased uptake of ES, OTA, and uric acid; and the T392I variant, whose reduced function is caused by impaired expression of the transporter membrane.

Numerous questions, including what causes this change in function and why the alterations occur, remain unanswered in the study of genetic polymorphisms and their impacts.

Drug-drug interactions

OATs have a wide spectrum of substrate recognition, therefore when administered together, different drugs may interact—either in a competitive or non-competitive way—with the same transporters, which can lead to mutually affecting each other’s pharmacokinetic profiles^[1]. These interactions involve inhibitors and activators of OATs, discussed in the previous section.

Disease states^[1]

Kidney disorders and other diseases can significantly change the expression and activity of OATs, changing their function and ultimately impacting how the body handles different substances.

Acute kidney injury is caused by drug/toxin-induced renal toxicity and renal ischemia, and usually produces a decrease in the glomerular filtration rate and affects secretion and absorption in the renal tubules. Decreased levels of mRNA and protein expression of OAT1 and OAT3 have been observed in patients with this disease, being one of the possible explanations for this that the toxicity is caused by gentamicin, and this antibiotic down-regulates the expression of the transporters, which also contributes to the development of the disease by the reduction in renal function.

Chronic kidney failure produces a gradual decrease in glomerular filtration rate and renal clearance, resulting in the accumulation of various toxins and endogenous substances, leading to renal failure. It is believed that the buildup of toxins and metabolites is what causes the mRNA and protein expression of OAT1 and OAT3 to decline in people with this illness, inhibiting, in addition, the transport produced by the OATs.

In addition to renal diseases, alterations in OATs have been observed in patients with diabetes and cholestasis, observing a reduction in mRNA and protein expression levels of OAT1, OAT2 and OAT3 in the first condition. Cholestasis is a liver disease in which the flow of bile from the liver is reduced or obstructed, and reduced levels of protein expression of OAT1 and OAT3 have been observed.

These findings show that, in order to effectively treat patients with any of these diseases, drug dosages must be modified while accounting for the glomerular filtration rate and OAT expression.

Sex

Differences in mRNA and protein expression of OAT1, OAT2 and OAT3 have been identified between female and male mice, suggesting the possible regulatory role of sex hormones^[4]. Research has revealed that male mice's kidneys express more OAT1 and OAT3 than those of female mice, which may be a sign of androgen stimulation and estrogen inhibition. On the other hand, OAT2 expression has been found to be higher in females than in males, suggesting that androgen inhibition and estrogen and progesterone stimulation may be occurring^[5].

Despite these results, research is still ongoing to determine the reasons for the reported variations in OAT expression between the sexes as well as why these inhibitions and stimulations occur.

OAT family

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References

1. ↑ ^{1.0 1.1 1.2 1.3} Zhang, J., Wang, H., Fan, Y., Yu, Z., & You, G. (2021). Regulation of organic anion transporters: Role in physiology, pathophysiology, and drug elimination. Pharmacology & therapeutics, 217, 107647. https://doi.org/10.1016/j.pharmthera.2020.107647
2. ↑ ^{2.0 2.1} Koepsell, H. (2013). The SLC22 family with transporters of organic cations, anions and zwitterions. Molecular aspects of medicine, 34(2-3), 413-435. https://doi.org/10.1016/j.mam.2012.10.010
3. ↑ Li, Z., Lam, P., Zhu, L., Wang, K., & Zhou, F. (2012). Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs). Journal of Pharmacogenomics and Pharmacoproteomics, 3, 1-8. https://doi.org/10.4172/2153-0645.1000E127
4. ↑ Anzai, N., Kanai, Y., & Endou, H. (2006). Organic anion transporter family: current knowledge. Journal of pharmacological sciences, 100(5), 411-426. https://doi.org/10.1254/jphs.CRJ06006X
5. ↑ Ljubojevic, M., Balen, D., Breljak, D., Kusan, M., Anzai, N., Bahn, A., ... & Sabolic, I. (2007). Renal expression of organic anion transporter OAT2 in rats and mice is regulated by sex hormones. American Journal of Physiology-Renal Physiology, 292(1), F361-F372. https://doi.org/10.1152/ajprenal.00207.2006