title: Bilirubin participates in protecting of heme oxygenase-1 induction by quercetin against ethanol hepatotoxicity in cultured rat hepatocytes.
abstract: To attenuate alcohol liver disease (ALD) is extremely urgent since ALD has been emerged as a major liver disease. The aim of the present study is to investigate the hepatoprotective effect against ethanol-induced injury of bilirubin, a product of heme metabolism degradation via HO and biliverdin reductase catalysis. Ethanol-incubated primary rat hepatocytes (100 mmol/L) were treated by quercetin, bilirubin, inflammatory factors, and/or HO-1 inducer/inhibitor for 24 h, and the cellular damage was assayed. Quercetin lowered ethanol-induced glutathione depletion and superoxide dismutase inactivation, inhibited the overproduction of malondialdehyde and reactive oxygen species, and decreased the leakage of cellular aspartate aminotransferase and lactate dehydrogenase, accompanying the normalization of bilirubin level. The effect of quercetin was mimicked by exogenous bilirubin in a dose-dependent manner to some extent (within 25 μmol/L) and pharmacological HO-1 inducer hemin, but abolished by HO-1 inhibitor zinc protoporphyrin-IX. Inflammatory challenge of TNF-α plus IL-6 further aggravated ethanol-induced oxidative damage, which was also attenuated by bilirubin in part. These findings shed a light on the anti-oxidative and anti-inflammatory role of bilirubin released from quercetin/HO-1 and biliverdin reductase pathway against ethanol hepatotoxicity and highlight a prospective strategy of nutritional intervention for ALD by naturally occurring quercetin to induce HO-1 with the release of bioactive end-products.
authors.affiliation: Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Qinfeng
authors.initials: Q
authors.lastname: Jie
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Tang
authors.forename: Yue
authors.initials: Y
authors.lastname: Deng
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Yanru
authors.initials: Y
authors.lastname: Shi
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Mingyou
authors.initials: M
authors.lastname: Xing
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001663:Bilirubin / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology*; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D011794:Quercetin; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D005978:Glutathione; D001663:Bilirubin