Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

Christiane Pauli-Magnus, M.D.; Peter J. Meier, M.D.; Bruno Stieger, Ph.D.

Disclosures

Semin Liver Dis. 2010;30(2):147-159. 

In This Article

Pathophysiology of Steroid-induced Cholestasis

Clinical evidence based on serum levels of estrogens during pregnancy-linked steroid hormones with intrahepatic cholestasis of pregnancy.[68,69] Progesterone and its metabolites, in addition, could contribute to the pathogenesis of cholestasis of pregnancy.[51,64,70] Alternately, oral contraceptives can also lead to cholestasis.[69,71] In animal experiments, the steroid metabolites estradiol-17β-glucuronide and progesterone sulfate have been demonstrated to lead to acute cholestasis immediately after application.[48,72]

From studies with rats treated for 5 days with high (usually 50 mg/kg body weight) ethinylestradiol, a model for estrogen-induced cholestasis, the following pathophysiologic picture emerged: sodium-dependent uptake of taurocholate into basolateral liver plasma membrane vesicles is reduced by ~40% and the vmax of ATP-dependent bile salt transport into canalicular vesicles was reduced by 60%. Also, the transport of dinitrophenylglutathione was markedly reduced. These functional data were paralleled by a 40% decrease of bile flow.[73] Heterologous expression of cloned rat Mrp2 identified this transporter as responsible for dinitrophenylglutathione transport[74] and Bsep as the canalicular taurocholate transporter.[39] At the mRNA level, Ntcp, Oatp1a1, and Oatp1a4 are markedly downregulated after 5 days of ethinylestradiol treatment, while Oatp2b1 remains unchanged, which is mirrored at the protein levels of the respective transporters.[75–77] The canalicular transporters Bsep and Mrp2 remain unchanged at the mRNA level in this rat model, while protein levels are downregulated by ~40% for Bsep and by ~80% for Mrp2, respectively.[76,78] Also, the canalicular water channel aquaporin-8 is downregulated in the canalicular membrane leading to a reduced water permeability of this membrane.[79] The basolateral salvage transporter Mrp3 is massively upregulated in ethinylestradiol treated rats at the mRNA and protein level.[80,81] Therefore, high levels of estrogens clearly alter the expression pattern of key hepatocellular bile salt and drug transporters. Estradiol seems to act predominantly via estrogen receptor alpha, as in mice with a disrupted gene for this receptor neither the expression of the uptake transporters Ntcp, Oatp1a1, and Oatp1a4, nor the expression of the efflux transporter Bsep is affected.[82] In human females, the depot estrogen ethinylestradiol propanolsulphonate leads to a significant increase of total serum bile salts. Among the different bile salt species, the most pronounced effect was observed with taurine conjugates.[83] As this was paralleled with an increase in secondary bile salts, this study suggests a mild cholestatic phenotype due to the estrogen.

In a 5-day treatment regimen with ethinylestradiol of Wistar and TR rats, which lack functional Mrp2, cholestasis was observed in both strains.[84] In contrast, the acute cholestatic action of estradiol-17β-glucuronide critically depends on expression of Mrp2, as this estrogen metabolite does not cause cholestasis in TR rats.[49] In less than 30 minutes, treatment of rats with a bolus of estradiol-17β-glucuronide leads to a rapid internalization of a fraction of Mrp2 and Bsep into a subapical, vesicular compartment.[85–87] This internalization is dependent on Ca2 + -dependent protein kinase C.[88]

In summary, the molecular events in estrogen-induced cholestasis affect many transport systems in the basolateral and canalicular membrane, whereby the uptake side seems to be mainly affected at the transcriptional level, whereas in the canalicular export site posttranscriptional processes predominate.

Steroid-induced cholestasis is not exclusively associated with estrogens and/or progesterones. For example, the usage of androgenic or anabolic steroids by competitive and noncompetitive athletes or body builders[89,90,91] can lead to liver injury including bland cholestasis.[92] Liver injury by this class of steroids is typically induced by compounds, which are alkylated at the 17α-position. Androgenic or anabolic steroid-induced cholestasis can lead to severe jaundice,[93,94] which may be prolonged[95] and accompanied with severe pruritus.[96] The literature on pathogenetic mechanisms of androgenic or anabolic steroid-induced cholestasis is scarce. Evidence from rat studies has been presented that the pericanalicular microfilaments are lost.[97] Given the structural similarity of androgenic or anabolic steroids to estrogens, it is tempting to speculate that additionally similar mechanisms as with estrogens may apply to the pathogenesis of androgenic or anabolic steroid-induced cholestasis.

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