Genistein, Phycocyanobilin, and Melatonin May Prevent Hepatic Fibrosis by Suppressing Proliferation and Activation of Hepatic Stellate Cells

Hepatic fibrosis reflects hepatotoxin-mediated activation of hepatic stellate cells, resulting in their proliferation and transformation to myofibroblasts that secrete collagen. This activation is suppressed by estrogen, an effect which explains the decreased risk for hepatic fibrosis enjoyed by premenopausal women and by postmenopausal women receiving hormone replacement therapy. Since stellate cells have been found to express the beta but not the alpha isoform of the estrogen receptor, it can be predicted that nutritional intakes of the soy isoflavone genistein – a selective agonist for ERbeta in the low nanomolar plasma concentrations achievable with these intakes – have potential for suppressing hepatic fibrosis, in both men and women. The antiproliferative impact of estrogen on stellate cells is mediated at least in part by suppression of NADPH oxidase activity; oxidant production by this enzyme complex plays a crucial role in stellate cell activation. Alternatively, it may be feasible to inhibit NADPH oxidase with phycocyanobilin (PCB), a biliverdin homolog found in spirulina that has recently been shown to inhibit the NADPH oxidase activity of human cell cultures in low micromolar concentrations. The downstream effects of oxidants in stellate cells may be blunted by melatonin, which boosts expression of antioxidant enzymes in many tissues, and has demonstrated anti-fibrotic effects in rat models of hepatotoxicity. A regimen consisting of soy isoflavones, PCB, and nocturnal melatonin in appropriate doses might have considerable potential for prevention of hepatic fibrosis in at-risk subjects. Estrogen Retards Hepatic Fibrosis There is growing epidemiological evidence that premenopausal women afflicted with fibrogenic liver diseases such as hepatitis C are at lower risk for fibrosis and cirrhosis than are postmenopausal women or men with this disorder; furthermore, in postmenopausal women with hepatitis C, concurrent hormone replacement therapy is associated with slower progression of fibrosis. 1-3 This conclusion accords well with studies demonstrating that administration of estrogen or of estrogenic drugs attenuates hepatic fibrosis in rodents treated with hepatotoxic agents – whereas ovariectomy has the opposite effect. 3-7 A likely site of estrogen’s action in this regard is the hepatic stellate cell, which, in response to numerous hepatotoxic agents, converts to a myofibroblast phenotype and proliferates, depositing the excessive collagen and other ground substance proteins observed in hepatic fibrosis. 8 In vitro, estrogen suppresses the proliferation and activation of stellate cells induced by various agents. 3;9;10 In aggregate, these findings have prompted suggestions that postmenopausal women with hepatitis C or other fibrogenic liver disorders should be treated with hormone replacement therapy (HRT). 1;2