Protective effect of heme oxygenase induction in ethinylestradiol‐induced cholestasis

Abstract

Estrogen-induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction of heme oxygenase-1 (HMOX1), the inducible isozyme in heme catabolism, is mediated via the Bach1/ Nrf2 pathway, and protects livers from toxic, oxidative and inflammatory insults. However, its role in cholestasis remains unknown. Here, we investigated the effects of HMOX1 induction by heme on ethinylestradiol-induced cholestasis and possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. HMOX1 was induced by heme (15 lmol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, hepatocyte and renal membrane transporter expression, and biliary and urinary bile acids excretion were quantified. Ethinylestradiol significantly increased cholestatic markers (P ≤ 0.01), decreased biliary bile acid excretion (39%, P = 0.01), down-regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P ≤ 0.05), and up-regulated Mrp3 (348%, P ≤ 0.05). Heme pre-treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P ≤ 0.05) and up-regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P ≤ 0.05) and ethinylestradiol-treated rats (512%, P ≤ 0.05). In primary rat hepatocytes, Nrf2 silencing completely abolished heme-induced Mrp3 expression. Additionally, heme significantly increased urinary bile acid clearance via up-regulation (Mrp2/Mrp4) or down-regulation (Mrp3) of renal transporters (P ≤ 0.05). We conclude that HMOX1 induction by heme increases hepatocyte transporter expression, subsequently stimulating bile flow in cholestasis. Also, heme stimulates hepatic Mrp3 expression via a Nrf2-dependent mechanism. Bile acids transported by Mrp3 to the plasma are highly cleared into the urine, resulting in normal plasma bile acid levels. Thus, HMOX1 induction may be a potential therapeutic strategy for the treatment of ethinylestradiol-induced cholestasis.

Genetic polymorphism of the Nrf2 promoter region is associated with vitiligo risk in Han Chinese populations

“…Many studies have examined the status of antioxidants and antioxidant enzymes in vitiligo patients [32]. Meanwhile, up-regulation of HO-1 may represent an attempt to minimize cellular injury [33]. In our previous study, we investigated the serum HO-1 activity in patients with vitiligo and controls, and a lower HO-1 activity was observed in vitiligo patients than in controls.…”

Activation of necroptosis in human and experimental cholestasis

“… 17 Finally, HO-1 has been suggested to stimulate bile flow during ethinylestradiol-induced cholestasis in rats. 39 …”

Induction of Mild Hyperbilirubinemia: Hype or Real Therapeutic Opportunity?

“…38 It is necessary to stress that HMOX1 induction does not probably lead to elevation of systemic bilirubin concentrations due to HMOX1 gene polymorphism 39 but also of intracellular bilirubin concentrations. 40 A large number of clinically used therapeutics has been reported to induce HMOX1, an activity that may at least partially account for their therapeutic effect ( Table 2). 38 Among others, these drugs include nonsteroidal anti-inflammatory drugs such as coxibs 41 or acetylsalicylic acid, 42 hypolipidemics such as niacin, 43 fibrates, 44 or statins.…”