Endocrine Regulation of Rat Organic Anion Transporters

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Messenger RNA levels of rat organic anion transporter 1 (Oat1; Slc22a6) and Oat2 (Slc22a7) in kidney and Oat3 (Slc22a8) in liver are gender-predominant. Oat1 and Oat3 are male-predominant, whereas Oat2 is female-predominant. Gonadectomized and hypophysectomized (HX) rats were studied to determine whether sex steroids and/or growth hormone (GH) are responsible for these gender-divergent patterns. GH was administered to HX rats by two daily injections (simulating male secretion) or continuous infusion (simulating female secretion). Oat1 mRNA levels, normally higher in male than female kidney, were lowered by gonadectomy and HX in male rats, but not in females. Additionally, GH injections or infusion did not alter Oat1 levels in HX rats. Oat2 mRNA levels, typically much higher in female than in male kidney, were unaffected by gonadectomy. However, HX dramatically decreased Oat2 in female kidney without altering male levels. GH administered by continuous infusion increased Oat2 in kidneys of both HX male and female rats, whereas injections had no affect. Gonadectomy reduced Oat3 mRNA levels in male livers without affecting levels in female livers. In contrast, HX decreased male and elevated female Oat3 mRNA. GH injections did not significantly change Oat3 mRNA levels in HX rats, but infusion decreased Oat3 mRNA in liver. In conclusion, androgens, but not GH, are responsible for the Oat1 mRNA gender difference in kidney; the female GH secretion pattern is responsible for the Oat2 mRNA gender difference in kidney; and both androgens and the female GH secretion pattern are responsible for the Oat3 mRNA gender difference in liver.Metabolism and excretion both determine elimination of endogenous and exogenous compounds. Liver is the primary site of metabolism, and liver and kidney are important organs in the process of excretion. Increasing or decreasing metabolism or excretion can lead to a respective decrease or increase of xenobiotic half-life, thus altering disposition. Expression of phase I [e.g., cytochromes P450 (P450s 1 )] and phase II enzymes [e.g., glucuronosyltransferases and sulfotransferases (STs)] is critical to metabolic processes, whereas transport proteins are vital for excretion. Interestingly, some enzymes and transporters are expressed in a gender-specific manner.

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

“…In addition, in contrast to renal rOat2, testosterone increased rOat3 mRNA levels in the liver of male rats [124]. Consistent with this observation, gonadectomy reduced hepatic rOat3 mRNA levels in males [125]. In contrast, gonadectomy did not affect rOat3 mRNA levels in female livers [125].…”

“…Consistent with these findings, administration of estradiol or progesterone to castrated or noncastrated male rats weakly stimulated renal rOat2 mRNA and protein expression [126,127]. In addition, it has been shown that the growth hormone secretion pattern is an important determinant of rOat2 message expression [125]. In particular, continuous growth hormone secretion, as is seen only in females, appears to be important for rOat2 renal expression.…”

“…In the first assessment, it was found that renal rOat1 mRNA levels were not different between male and female rats [124]. However, in several subsequent reports, male rats and mice exhibited higher mRNA levels [55,56,125]. Furthermore, a reduction in rOat1 mRNA via gonadectomy in males confirmed that this difference was due to greater androgen levels in males [125].…”

“…In such a case, it will be of interest to determine the mechanism supporting this organ-specific gender-dependent regulation. As alluded to above, renal Oat2 mRNA and protein was reported to be predominant in female rats and mice [56,[124][125][126][127]. Castration of male rats markedly increased renal rOat2 mRNA and protein [126,127], whereas ovariectomy in females resulted in a relatively weak reduction in rOat2 mRNA and protein [126].…”

“…Hepatic rOat3/mOat3 mRNA was reported to be exclusive to, or much more abundant in males [56,124,125]; however, hypophysectomy (pituitary gland removal) triggered rOat3 mRNA expression in the liver of females [124,125]. Furthermore, hypophysectomy decreased male rOat3 mRNA expression in the liver [125].…”