Sex-dependent expression and growth hormone regulation of class alpha and class mu glutathione S-transferase mRNAs in adult rat liver

Srivastava, P. K.; Waxman, David J.

doi:10.1042/bj2940159

Cited by 53 publications

(44 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In humans, serum bilirubin levels are significantly lower in females and bilirubin clearance is greater (4,51). In addition, studies in rats have shown that GSTA1 and UGT1A1 are greater in females compared with males (49,70), whereas only one study has addressed possible gender differences in the expression of Mrp2 (32). Therefore, we examined the hypothesis that Mrp2 expression was similarly increased in female rats compared with males.…”

Section: Discussionmentioning

confidence: 99%

Hormonal regulation of hepatic multidrug resistance-associated protein 2 (Abcc2) primarily involves the pattern of growth hormone secretion

Simon¹,

Iwahashi²,

Hu³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Biliary excretion is the rate-limiting step in transfer of bilirubin, other organic anions, and xenobiotics across the liver. Multidrug resistance-associated protein 2 (Mrp2, Abcc2) is the major transporter for conjugated endo- and xenobiotic-conjugated compounds into bile. Hormones regulate bilirubin and xenobiotic secretion into bile, which have dimorphic differences. Therefore, we examined the possible role of sex steroids and growth hormone in the regulation of Mrp2. In ∼8-wk-old rats, mRNA, transcriptional activity, and hepatic content of Mrp2 were selectively increased fourfold ( P < 0.001) in females compared with males. In males, estrogens increased and testosterone decreased Mrp2 mRNA and protein, whereas no significant effect was measured in females, suggesting either a direct effect on the liver or an alteration in growth hormone secretory pattern. After hypophysectomy, Mrp2 mRNA was markedly reduced and the effects of estrogens and testosterone on Mrp2 were prevented, supporting the role of pituitary hormones in controlling Mrp2 expression. Mrp2 increased following growth hormone infusion in males. Mrp2 mRNA was decreased in growth hormone-deficient “Little” mice. Growth hormone infusions in hypophysectomized rats partially restored Mrp2 levels, whereas thyroxine addition returned Mrp2 mRNA and protein to basal levels. Morphology as well as biochemical measurements demonstrated that Mrp2 was localized to the bile canaliculus in equal density in both genders, whereas hormone replacements increased Mrp2 in hypophysectomized animals. In cultured hepatocytes, thyroxine did not have an effect, but growth hormone alone and combined with thyroxine increased Mrp2 mRNA levels. In conclusion, Mrp2 levels are regulated by the combination of thyroxine and different growth hormone secretory patterns.

show abstract

Section: Discussionmentioning

confidence: 99%

Hormonal regulation of hepatic multidrug resistance-associated protein 2 (Abcc2) primarily involves the pattern of growth hormone secretion

Simon¹,

Iwahashi²,

Hu³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…Studies carried out in rats and mice have established that sex-based differences in liver function also characterize many phase II DMEs, including sulfotransferases (Klaassen et al, 1998;Clodfelter et al, 2006;Kocarek et al, 2008), glutathione transferases (Srivastava and Waxman, 1993;Clodfelter et al, 2006;Knight et al, 2007), and UDP-glucuronosyltransferases (Takeuchi et al, 2004;Clodfelter et al, 2006;Buckley and Klaassen, 2007). In addition to drugs and other xenobiotics, P450s and other DMEs metabolize endogenous sex steroids (Waxman, 1988;Song and Melner, 2000;You, 2004;Chouinard et al, 2008), suggesting that the sex differentiation of drug metabolism reflects a need for sex-specific steroid metabolism.…”

Section: Sex Differences In Hepatic Drug Metabolismmentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

621

584

View full text Add to dashboard Cite

Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

show abstract

“…Gender-divergent expression regulated by growth hormone secretion was reported for P450s (Pampori and Shapiro, 1999), Sults (Liu and Klaassen, 1996;Alnouti and Klaassen, 2006), Ugts (Buckley andGsts (Srivastava andWaxman, 1993;Knight et al, 2007), as well as xenobiotic transporters (Tanaka et al, 2005;Cheng et al, 2006;Maher et al, 2006). Because of the altered sex hormone and growth hormone levels in old age (Rudman et al, 1990;Bjørnerem et al, 2004), it is important to investigate the gender differences in XPG expression during aging.…”

Section: Introductionmentioning

confidence: 99%

Effects of Aging on mRNA Profiles for Drug-Metabolizing Enzymes and Transporters in Livers of Male and Female Mice

Csanaky²,

Klaassen³

2012

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Aging is a physiological process characterized by progressive functional decline in various organs over time. To reveal possible molecular mechanisms of altered xenobiotic disposition and toxicity in elderly individuals, age-dependent mRNA profiles for 101 xenobiotic-processing genes (XPGs), including seven uptake transporters, 41 phase I enzymes, 36 phase II enzymes, 10 efflux transporters, and seven transcription factors, were characterized in livers of male and female mice from 3 to 27 months of age. Gender differences across the lifespan (significant at five ages or more) were observed for 52 XPGs, including 15 male-predominant genes (e.g., Oatp1a1, Cyp3a11, Ugt1a6a, Comt, and Bcrp) and 37 female-predominant genes (e.g., Oatp1a4, Cyp2b10, Sult1a1, Ugt1a1, and Mrp3). During aging, the mRNA levels for 44% of the 101 XPGs changed in male mice and 63% changed in female mice. In male mice, mRNA levels for 40 XPGs (e.g., Oatp1a1, Ces2c, Gstm4, Gstp1, and Ces1e) were lower in aged mice (more than 21 months of age), whereas mRNA levels for four XPGs (e.g., Oat2 and Gstm2) were higher in aged mice. In female mice, mRNA levels for 43 XPGs (e.g., Oatp1a1, Cyp1a2, Ces1f, Sult3a1, Gstt2, Comt, Ent1, Fmo3, and Mrp6) were lower in aged mice, whereas mRNA levels for 21 XPGs (e.g., Oatp1a4, Nqo1, Adh7, Sult2a1/2, Gsta1, and Mrp4) were higher in aged mice. In conclusion, 51% of the 101 XPGs exhibited gender differences in liver mRNA levels across the lifespan of mice; the mRNA levels for 40% of the XPGs were lower in aged male mice and 43% were lower in aged female mice.

show abstract

Sex-dependent expression and growth hormone regulation of class alpha and class mu glutathione S-transferase mRNAs in adult rat liver

Cited by 53 publications

References 36 publications

Hormonal regulation of hepatic multidrug resistance-associated protein 2 (Abcc2) primarily involves the pattern of growth hormone secretion

Hormonal regulation of hepatic multidrug resistance-associated protein 2 (Abcc2) primarily involves the pattern of growth hormone secretion

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Effects of Aging on mRNA Profiles for Drug-Metabolizing Enzymes and Transporters in Livers of Male and Female Mice

Contact Info

Product

Resources

About