Endocrine Regulation of Gender-Divergent Mouse Organic Anion-Transporting Polypeptide (Oatp) Expression

Cheng, Xinjian; Maher, Jonathan; Lü, Hong; Klaassen, Curtis D.

doi:10.1124/mol.106.025122

Cited by 43 publications

(31 citation statements)

References 49 publications

(64 reference statements)

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“…Oatp1a1 and Oatp1a3 are expressed on apical membranes of proximal tubules in rats (Bergwerk et al, 1996), and lower expression of Oatp1a1 in female rats was proposed to be relevant to the higher urinary excretion of its substrates (Gotoh et al, 2002;Kato et al, 2002). In mouse kidney, gene expression of Oatp1a1 is also higher in males than females (Cheng et al, 2006). However, in the present study, no gender difference was observed in plasma and kidney concentrations or urinary excretion of CER (Fig.…”

Section: Discussioncontrasting

confidence: 49%

Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice

Kano

Kato²,

Ito³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Carnitine/organic cation transporter (OCTN) 2 (SLC22A5) plays a pivotal role in renal tubular reabsorption of carnitine, a vitamin-like compound, on apical membranes of proximal tubules, but its role in relation to therapeutic drugs remains to be clarified. The purpose of the present study was to elucidate the involvement of OCTN2 in renal disposition of a ␤-lactam antibiotic, cephaloridine (CER), based on experiments with juvenile visceral steatosis (jvs) mice, which have a functional deficiency of the octn2 gene. Renal clearance of CER during constant intravenous infusion in wild-type mice was much higher than could be accounted for by glomerular filtration, but was decreased by increasing the infusion rate with minimal change in kidney-to-plasma concentration ratio, suggesting the existence of saturable transport mechanism(s) across the apical membranes. The plasma concentration profile and kidneyto-plasma concentration ratio after intravenous injection in jvs mice were higher than those in wild-type mice, whereas renal clearance in jvs mice was much lower than that in wild-type mice and could be accounted for by glomerular filtration. Uptake of CER by mouse OCTN2 was shown in Xenopus laevis oocytes expressing mouse OCTN2. The CER transport by OCTN2 exhibited saturation with K m of ϳ3 mM, which is similar to the renal CER concentration exhibiting saturation in renal clearance in vivo. The OCTN2-mediated CER transport was inhibited by carnitine and independent of Na ؉ replacement in the medium. These results show OCTN2 on apical membranes of proximal tubules plays a major role in renal secretion of CER in mice.

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Section: Discussioncontrasting

confidence: 49%

Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice

Kano

Kato²,

Ito³

et al. 2009

Drug Metab Dispos

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“…More recently, regulation of several mouse Cyps and solute carriers by Stat5b were further characterized in Stat5b-deficient mice (Clodfelter et al, 2006). In kidney, gender-specific gene expression is primarily attributed to the actions of sex hormones (androgens and estrogens), as reported for rat Oats, mouse Oatps, and mouse Mrps (Buist et al, 2003;Ljubojevic et al, 2004;Cheng et al, 2006;Maher et al, 2006).…”

mentioning

confidence: 98%

“…Gender-divergent gene expression in liver has been characterized for many rodent genes whose proteins are involved in drug metabolism and disposition, such as cytochromes P450 (P450s), multidrug resistance-associated proteins (Mrps), and organic anion-transporting polypeptides (Oatps) (Waxman et al, 1991;Cheng et al, 2006;Maher et al, 2006). Likewise, previous studies report gender-divergent mRNA expression patterns for both rat and mouse UGTs (Shelby et al, 2003;Buckley and Klaassen, 2007).…”

mentioning

confidence: 99%

Mechanism of Gender-Divergent UDP-Glucuronosyltransferase mRNA Expression in Mouse Liver and Kidney

Buckley

Klaassen

2009

Drug Metab Dispos

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ABSTRACT:UDP-glucuronosyltransferases (UGTs) catalyze the addition of glucuronic acid to endo-and xenobiotics, increasing hydrophilicity and enhancing elimination. Gender-divergent glucuronidation rates are observed in humans and rats, and gender differences in UGT mRNA levels have been observed in rodents. The purpose of this study was to establish the hormonal regulation of genderdependent Ugt mRNA expression in mouse liver and kidney. Therefore, three mouse models were used to characterize the involvement of sex hormones and gender-specific growth hormone (GH) secretion patterns, including 1) hypophysectomized mice treated with male-or female-pattern GH, testosterone, or 17␤-estradiol; 2) GH releasing hormone receptor-deficient little (lit/lit) mice treated with male-or female-pattern GH; and 3) gonadectomized mice treated with testosterone or 17␤-estradiol. Messenger RNA expression of mouse Ugt isozymes was determined by the branched DNA assay. In C57BL/6 mice, male-predominant expression of Ugt2b1 and Ugt2b38 was observed in liver and kidney, respectively. Female-predominant expression was observed for Ugt1a1 and Ugt1a5 in liver and Ugt1a2 in kidney. In liver, regulation of Ugt1a1 and Ugt1a5 expression was attributed to repression of Ugt mRNA by male-pattern GH secretion. Conversely, regulation of Ugt2b1 expression in liver was attributed to male-pattern GH secretion. In kidney, regulation of Ugt2b38 expression was attributed to inductive effects by testosterone. Conversely, Ugt1a2 expression in kidney was negatively regulated by testosterone. In conclusion, gender differences in mouse Ugt mRNA expression were influenced by male-pattern GH secretion in liver, whereas gender differences were regulated by the effects of androgens in kidney.UDP-glucuronosyltransferases (UGTs) are a family of microsomal enzymes that catalyze the addition of the high-energy cosubstrate UDP-glucuronic acid to endogenous and exogenous substrates, increasing their hydrophilicity and eventual excretion. UGT genes are composed of two major drug-metabolizing subfamilies, UGT1 and UGT2 (Mackenzie et al., 2005). UGT1 genes are unique in that each consists of a unique first exon and 5Ј-regulatory region; however, each is spliced with common exons 2 through 5. UGT1 enzymes conjugate a variety of compounds, particularly prescribed drugs, such as acetaminophen, and the endogenous heme-byproduct, bilirubin. In contrast, UGT2 genes each contain six individual exons, and UGT2 isozymes conjugate many endogenous steroids and exogenous substrates, such as morphine (Burchell et al., 1995;Tephly et al., 1998;Radominska-Pandya et al., 1999).In clinical studies, numerous glucuronidated drugs exhibit genderrelated differences in metabolism. For example, the benzodiazepine S-oxazepam, a UGT2B15 substrate, is glucuronidated at a higher rate in human liver microsomes from males than females (Court et al.,

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“…lit/lit mice (GHreleasing hormone receptor mutant heterozygous mice, C57BL/6J-Ghrhr lit ) were purchased from The Jackson Laboratory. The doses and routes of treatment of sex hormones and growth hormone in these mouse models have been reported previously (Cheng et al, 2006). After treatment, livers were removed for total RNA isolation.…”

Section: Animals and Treatmentmentioning

confidence: 99%

Hormonal and Chemical Regulation of Paraoxonases in Mice

Cheng

Klaassen

2012

J Pharmacol Exp Ther

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In humans and rodents, paraoxonase (PON/Pon) 1 expression and activity in livers and serum are higher in females than in males, and some drugs increase paraoxonase's expression. However, the underlining mechanisms of gender-divergent expression and chemical regulation of Pon1 remain largely unknown. The present study determined the regulatory mechanisms contributing to gender-divergent and chemically altered Pon expression in mouse livers. Pon1 mRNA was much more abundant in the livers of mice than other tissues, with higher levels in female livers than male livers at mRNA and protein levels. Pon2 mRNA was ubiquitously expressed in mouse tissues, but minimally in mouse liver. Pon3 mRNA was most abundant in mouse lung and liver and less abundant in other tissues. Pon1 mRNA was lowest in fetal liver, markedly increased at parturition, and remained relatively constant thereafter. Pon2 and Pon3 mRNA are highly expressed in fetal liver and decreased after birth. Male-pattern growth hormone (GH) administration in hypophysectomized and lit/lit mice decreased Pon1 expression. Sex hormones and female-pattern GH administration had no effect on Pon1 expression, indicating the importance of male-pattern GH in regulating Pon1. Aryl hydrocarbon receptor, pregnane X receptor, and NF-E2-related factor activators had no effect on Pon1 mRNA. A constitutive androstane receptor (CAR) activator decreased Pon1 expression in wild-type but not CAR-null mice. In conclusion, Pon1 mRNA was most abundant in adult mouse livers, whereas Pon2 and Pon3 mRNAs were most abundant in fetal mouse livers. Female-predominant Pon1 expression in mouse livers is caused by the inhibitory effects of male-pattern GH secretion, and CAR activation decreases Pon1 expression.

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Endocrine Regulation of Gender-Divergent Mouse Organic Anion-Transporting Polypeptide (Oatp) Expression

Cited by 43 publications

References 49 publications

Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice

Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice

Mechanism of Gender-Divergent UDP-Glucuronosyltransferase mRNA Expression in Mouse Liver and Kidney

Hormonal and Chemical Regulation of Paraoxonases in Mice

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