title: Comparative metabolism of honokiol in mouse, rat, dog, monkey, and human hepatocytes.
abstract: Honokiol has antitumor, antioxidative, anti-inflammatory, and antithrombotic effects. Here we aimed to identify the metabolic profile of honokiol in mouse, rat, dog, monkey, and human hepatocytes and to characterize the enzymes responsible for the glucuronidation and sulfation of honokiol. Honokiol had a high hepatic extraction ratio in all five species, indicating that it was extensively metabolized. A total of 32 metabolites, including 17 common and 15 different metabolites, produced via glucuronidation, sulfation, and oxidation of honokiol allyl groups were tentatively identified using liquid chromatography-high resolution quadrupole Orbitrap mass spectrometry. Glucuronidation of honokiol to M8 (honokiol-4-glucuronide) and M9 (honokiol-2'-glucuronide) was the predominant metabolic pathway in hepatocytes of all five species; however, interspecies differences between 4- and 2'-glucuronidation of honokiol were observed. UGT1A1, 1A8, 1A9, 2B15, and 2B17 played major roles in M8 formation, whereas UGT1A7 and 1A9 played major roles in M9 formation. Human cDNA-expressed SULT1C4 played a major role in M10 formation (honokiol-2'-sulfate), whereas SULT1A1*1, 1A1*2, and 1A2 played major roles in M11 formation (honokiol-4-sulfate). In conclusion, honokiol metabolism showed interspecies differences.
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Republic of Korea.
authors.forename: Hyeon-Uk
authors.initials: HU
authors.lastname: Jeong
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Republic of Korea.
authors.forename: Ju-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Republic of Korea.
authors.forename: Tae Yeon
authors.initials: TY
authors.lastname: Kong
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Republic of Korea.
authors.forename: Won Gu
authors.initials: WG
authors.lastname: Choi
authors.affiliation: Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon, 420-743, Republic of Korea. sianalee@catholic.ac.kr.
authors.forename: Hye Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000378:metabolism*; D001711:Biotransformation; D001713:Biphenyl Compounds / Q000378:metabolism*; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D000882:Haplorhini; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D017705:Lignans / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D051381:Rats; D013045:Species Specificity; D013463:Sulfuric Acid Esters / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D015239:Arylsulfotransferase; D001713:Biphenyl Compounds; D020719:Glucuronides; D014453:Glucuronosyltransferase; D017705:Lignans; D013463:Sulfuric Acid Esters; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols
keywords: Comparative metabolism; Hepatocytes; Honokiol; Sulfotransferases; UDP-glucuronosyltransferases