Transport of dehydroepiandrosterone and dehydroepiandrosterone sulphate into rat hepatocytes

Reuter, Stephan; Mayer, Doris

doi:10.1016/0960-0760(95)00132-j

Cited by 25 publications

(14 citation statements)

References 23 publications

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“…The differential activities of DHEA and DHEA-S in vivo versus cultured cell lines may be due to differential abilities to transport DHEA-S. DHEA is expected to pass through the cell membrane by diffusion because it is a lipophilic compound. However, DHEA-S is taken up by active transport (Reuter and Mayer, 1995). The organic anion transport systems that transport DHEA-S may be lost in cultured cell lines.…”

Section: Fig 4 Concentration-dependent Activation Of Pxr By Dhea Amentioning

confidence: 99%

Induction of CYP3A Expression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor

Ripp

Fitzpatrick

Peters³

et al. 2002

Drug Metabolism and Disposition

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ABSTRACT:Dehydroepiandrosterone (DHEA) is a steroid produced by the human adrenal gland. Administration of pharmacological doses of DHEA to rats changes expression of many genes, including the cytochrome P450 family members CYP4A1 and CYP3A23. It is known that induction of CYP4A expression by DHEA requires the peroxisome proliferator-activated receptor ␣ (PPAR␣). In the current study, PPAR␣-null mice were used to examine the role of PPAR␣ in expression of CYP3A. In wild-type mice, 150 mg/kg DHEA-sulfate induced Cyp4a and Cyp3a11 mRNAs by 5-and 2-fold, respectively. Induction of Cyp4a expression by DHEA-sulfate was not observed in PPAR␣-null mice, whereas induction of Cyp3a11 expression by DHEA-sulfate was similar between genotypes. This suggests that PPAR␣ is not involved in induction of Administration of dehydroepiandrosterone (DHEA 2 ) to rodents results in several beneficial biological responses. DHEA acts as a chemopreventive agent in rodent cancer models (Schwartz, 1979;Schwartz and Tannen, 1981;Nyce et al., 1984;Pashko et al., 1984). Rodents with a predisposition toward obesity demonstrate decreased rates of weight gain without appetite suppression upon treatment with DHEA (Yen et al., 1977). Administration of DHEA ameliorated symptoms of diabetes and systemic lupus erythematosis in the appropriate rodent models (Coleman et al., 1982;Lucas et al., 1985). DHEA may act as a neurosteroid, and is thought to enhance memory function (Robel and Baulieu, 1995), as well as immune function (Morfin and Courchay, 1994).DHEA is the most abundant circulating steroid in humans. It is secreted by the adrenal gland as the 3␤-sulfate conjugate. DHEAsulfate (DHEA-S) is taken up by target tissues (e.g., testis and ovary), and hydrolyzed by sulfatases back to DHEA (Kroboth et al., 1999). DHEA can then be further metabolized to active androgens and estrogens in steroidogenic tissues, as well as to several hydroxylated metabolites in liver (Fitzpatrick et al., 2001).In rodents, DHEA is not produced by the adrenal, but limited amounts of DHEA are produced from progesterone in steroidogenic tissues (Pelletier et al., 1992;van Weerden et al., 1992). Although treatment of rodents with exogenous DHEA can produce the beneficial effects described above, high doses of DHEA induce peroxisome proliferation (Wu et al., 1989;Prough et al., 1994). Peroxisome proliferators, including DHEA, modulate expression of genes involved in fatty acid metabolism, including fatty acyl CoA oxidase, cytochrome P450 4A (CYP4A), and malic enzyme (Webb et al., 1996).3 DHEA and other peroxisome proliferators require the perox- drost-5-en-17-one); DHEA-S, dehydroepiandrosterone 3␤-sulfate; PPAR␣, peroxisome proliferator-activated receptor ␣; PXR, pregnane X receptor; ADIOL, androst-5-ene-3␤,17␤-diol; ADIONE, androst-4-ene-3,17-dione; 11␤-hydroxy-DHEA, 3␤,11␤-dihydroxy-androst-5-en-17-one; 16␣-hydroxy-DHEA, 3␤,16␣-dihydroxy-androst-5-en-17-one; 7-oxo-DHEA, 3␤-hydroxy-androst-5-ene-7,17-dione; 7␣-hydroxy-DHEA, 3␤,7␣-dihydroxy-androst-5-en-17-one; DMSO, dimethyl s...

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Section: Fig 4 Concentration-dependent Activation Of Pxr By Dhea Amentioning

confidence: 99%

Induction of CYP3A Expression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor

Ripp

Fitzpatrick

Peters³

et al. 2002

Drug Metabolism and Disposition

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“…The majority of DHEAS is formed in the liver from the sulfation of DHEA, after which it is effluxed back into the circulation across the sinusoidal surface of the hepatocyte (33). Furthermore, taurocholate inhibitable DHEAS uptake into isolated rat hepatocytes is also known to occur (34). Because members of this family are bi-directional transporters, OATP2 along with OATP are candidates for either of these transport processes in humans.…”

Section: Fig 3 Nucleotide and Amino Acid Sequence Of Human Oatp2mentioning

confidence: 99%

A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

Hsiang¹,

Zhu²,

Wang³

et al. 1999

Journal of Biological Chemistry

585

105

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A novel human organic transporter, OATP2, has been identified that transports taurocholic acid, the adrenal androgen dehydroepiandrosterone sulfate, and thyroid hormone, as well as the hydroxymethylglutaryl-CoA reductase inhibitor, pravastatin. OATP2 is expressed exclusively in liver in contrast to all other known transporter subtypes that are found in both hepatic and nonhepatic tissues. OATP2 is considerably diverged from other family members, sharing only 42% sequence identity with the four other subtypes. Furthermore, unlike other subtypes, OATP2 did not transport digoxin or aldosterone. The rat isoform oatp1 was also shown to transport pravastatin, whereas other members of the OATP family, i.e. rat oatp2, human OATP, and the prostaglandin transporter, did not. Cis-inhibition studies indicate that both OATP2 and roatp1 also transport other statins including lovastatin, simvastatin, and atorvastatin. In summary, OATP2 is a novel organic anion transport protein that has overlapping but not identical substrate specificities with each of the other subtypes and, with its liver-specific expression, represents a functionally distinct OATP isoform. Furthermore, the identification of oatp1 and OATP2 as pravastatin transporters suggests that they are responsible for the hepatic uptake of this liver-specific hydroxymethylglutaryl-CoA reductase inhibitor in rat and man.

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“…b) DHEA-S might act in liver or other tissues to stimulate production of another endogenous chemical that serves as a proximal PPARa activator. c) The entry of DHEA-S into cells may require a specific plasma membrane transporter that is known to be present in hepatocytes (40), but may be absent in COS-1 and other cell types used for PPAR transfection studies. Finally, d) DHEA-S may be converted to an activated metabolite by a metabolic process which occurs in hepatocytes but not in the cell lines used for transfection studies.…”

Section: Hydrocarbonsmentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptors by Chlorinated Hydrocarbons and Endogenous Steroids

Zhou¹,

Waxman²

1998

Environmental Health Perspectives

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Transport of dehydroepiandrosterone and dehydroepiandrosterone sulphate into rat hepatocytes

Cited by 25 publications

References 23 publications

Induction of CYP3A Expression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor

Induction of CYP3A Expression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor

A Novel Human Hepatic Organic Anion Transporting Polypeptide (OATP2)

Activation of Peroxisome Proliferator-Activated Receptors by Chlorinated Hydrocarbons and Endogenous Steroids

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