title: Sulfation of buprenorphine, pentazocine, and naloxone by human cytosolic sulfotransferases.
abstract: Buprenorphine, pentazocine, and naloxone are opioid drugs used for the treatment of pain and opioid dependence or overdose. Sulfation as catalyzed by the cytosolic sulfotransferases (SULTs) is involved in the metabolism of a variety of xenobiotics including drug compounds. Sulfation of opioid drugs has not been well investigated. The current study was designed to examine the sulfation of three opioid drugs, buprenorphine, pentazocine, and naloxone, in HepG2 human hepatoma cells and to identify the human SULT(s) responsible for their sulfation. Analysis of the spent media of HepG2 cells, metabolically labeled with [(35)S]sulfate in the presence of each of the three opioid drugs, showed the generation and release of their [(35)S]sulfated derivatives. A systematic analysis using eleven known human SULTs revealed SULT1A3 and SULT2A1 as the major responsible SULTs for the sulfation of, respectively, pentazocine and buprenorphine; whereas three other SULTs, SULT1A1, SULT1A2, and SULT1C4, were capable of sulfating naloxone. Enzymatic assays using combinations of these opioid drugs as substrates showed significant inhibitory effects in the sulfation of buprenorphine and pentazocine by naloxone. Differential sulfating activities toward the three opioid drugs were detected in cytosol or S9 fractions of human lung, liver, kidney, and small intestine. Collectively, these results imply that sulfation may play a role in the metabolism of buprenorphine, pentazocine, and naloxone in vivo.
authors.affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614, USA.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Kurogi
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Lee
authors.forename: Bo
authors.initials: B
authors.lastname: Shi
authors.forename: Teng
authors.initials: T
authors.lastname: Yan
authors.forename: Ming-Yih
authors.initials: MY
authors.lastname: Liu
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakakibara
authors.forename: Masahito
authors.initials: M
authors.lastname: Suiko
authors.forename: Ming-Cheh
authors.initials: MC
authors.lastname: Liu
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism; D002047:Buprenorphine / Q000008:administration & dosage / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D009270:Naloxone / Q000008:administration & dosage / Q000378:metabolism*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000378:metabolism; D010423:Pentazocine / Q000008:administration & dosage / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D013431:Sulfates; D009270:Naloxone; D002047:Buprenorphine; D015238:Sulfotransferases; D010423:Pentazocine