Hypericum perforatum L. and the Underlying Molecular Mechanisms for Its Choleretic, Cholagogue, and Regenerative Properties

Abstract

Any defects in bile formation, secretion, or flow may give rise to cholestasis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. As the pathogenesis of hepatic disorders is multifactorial, targeting parallel pathways potentially increases the outcome of therapy. Hypericum perforatum has been famed for its anti-depressive effects. However, according to traditional Persian medicine, it helps with jaundice and acts as a choleretic medication. Here, we will discuss the underlying molecular mechanisms of Hypericum for its use in hepatobiliary disorders. Differentially expressed genes retrieved from microarray data analysis upon treatment with safe doses of Hypericum extract and intersection with the genes involved in cholestasis are identified. Target genes are located mainly at the endomembrane system with integrin-binding ability. Activation of α5β1 integrins, as osmo-sensors in the liver, activates a non-receptor tyrosine kinase, c-SRC, which leads to the insertion of bile acid transporters into the canalicular membrane to trigger choleresis. Hypericum upregulates CDK6 that controls cell proliferation, compensating for the bile acid damage to hepatocytes. It induces ICAM1 to stimulate liver regeneration and regulates nischarin, a hepatoprotective receptor. The extract targets the expression of conserved oligomeric Golgi (COG) and facilitates the movement of bile acids toward the canalicular membrane via Golgi-derived vesicles. In addition, Hypericum induces SCP2, an intracellular cholesterol transporter, to maintain cholesterol homeostasis. We have also provided a comprehensive view of the target genes affected by Hypericum’s main metabolites, such as hypericin, hyperforin, quercitrin, isoquercitrin, quercetin, kaempferol, rutin, and p-coumaric acid to enlighten a new scope in the management of chronic liver disorders. Altogether, standard trials using Hypericum as a neo-adjuvant or second-line therapy in ursodeoxycholic-acid-non-responder patients define the future trajectories of cholestasis treatment with this product.

Acute Toxicity and Hepatoprotective Influence of Hypericum perforatum Against Thioactamid-Induced Liver Fibrosis in Rats

“…39 In contrast, rats that ingested silymarin or MEHP (250 and 500 mg/kg) showed significantly retained BW and liver weight almost near to normal values; this resistant effect of MEHP against TAA could be correlated with its phytochemical profile (hypericin, hyperforin, quercitrin, p -coumaric acid), which were repeatedly labeled as hepatoprotective agents. 15,40,41 Moreover, the present protective effect of MEHP on body and liver weight might be due to the antioxidant and anti-inflammatory potentials of their chemical contents, as previously detailed. 42,43…”

“…Despite previous reports on the therapeutic efficacy of H. perforatum against liver disorders, cholestasis, 15 and hepatitis B virus, 30 the literature data lacks a concise study detailing the possible molecular mechanisms behind hepatoprotection action of H. perforatum. Therefore, the present study investigates the hepatoprotective potentials of H. perforatum in TAA-stimulated liver injury in rats.…”

“…14 In the last few decades, numerous plant species were explored and reported as hepatoprotective products including those belonging to the genus Hypericum spp. 13,15…”

“…Hypericum perforatum ( Merr.) is a well-known therapeutic traditional Islamic medicine, Chinese medicine, and Greek medicine 15 that has been utilized for the attenuation of liver-related disorders, including hepatic dysfunctionality, steatosis, cholestasis, and liver fibrosis. 16 This plant species belongs to Hypericaceae (Clusiacaeae) family commonly known as St. John's wort (SJW) ( Hypericum or Millepertuis).…”

Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation

“…Furthermore, a correlation between heat shock protein 90 (HSP90) and hepatic injury was previously reported, and it was observed that HSP90 inhibitors exhibited a protective effect on various organs [120,121]. Additionally, the EGFR is implicated in the pathogenesis of both cirrhosis and hepatocellular carcinoma (HCC), with its hepatic expression increasing during cirrhosis [122].…”