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.

Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis

“…Oxymorphone [33], acetaminophen, minoxidil [11] Brain, rectum,stomach, cecum, jejunum, ileum,colon, liver [34,168], adrenal, kidney [169], lung [170] a hSULT1A2 Phenols e Naloxone [171], 2-naphthol, minoxidil [172] cecum, liver [168], kidney, lung [169] hSULT1A3 Catecholamines Dopamine, norepinephrine [174],iodothyronines [167] 6-hydroxydopamine [173], hydromorphone [33], isoprenaline [159] Rectum, colon cecum, jejunum ileum, stomach [168] lung [170], brain [34] ovary, oral mucosa [169] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 isoforms (Table 1). In contrast to hSULT1E1's high level of activity toward estrogens, hSULT1B1 is unable to sulfate estrogenic steroids [31,32].…”

Mechanism of sulfotransferase pharmacogenetics in altered xenobiotic metabolism

“…This list includes some common drugs, such as paracetamol (acetaminophen), used widely as an over-the-counter analgesic and antipyretic [9,10]. Paracetamol combined with opioid sulfate analgesics, such as morphine, naltrexone, naloxone and buprenorphine [11,12], is used in managing severe pain such as postsurgical pain and providing palliative care in advanced cancer patients [13]. The other SULT drug substrates, such as diflunisal, are used as analgesics and anti-inflammatory drugs [14].…”

“…The enzyme kinetics parameters have been determined, but are not shown in this Moderate-to-severe pain [11] Buprenorphine Opioid pain medication Moderate-to-severe pain [11] *The common drugs as sulfotransferase (SULT) substrates, their structures, their pharmacological functions for diseases were collected from various references. Some drugs are active only after sulfation modification.…”

Sulfation of opioid drugs by human cytosolic sulfotransferases: Metabolic labeling study and enzymatic analysis

“…Nevertheless, the metabolism of those three opioid drugs through sulfation has not been well studied in human and the responsible SULT(s) for the sulfation of those three opioid drugs as well as morphine even still remained to be clarified. Recently, we have demonstrated the sulfation of opioid drugs, buprenorphine, pentazocine, and naloxone using human hepatocyte and tissue cytosols, and determined the responsible SULT enzymes (Kurogi et al, 2012). It is therefore possible that SULT-mediated sulfation may be involved in the metabolism of not only morphine, hydromorphone, levorphanol, nalorphine, but also other opioid drugs including oxymorphone, butorphanol, nalbuphine, nalorphine, and naltrexone.…”

“…In contrast, SULT2A1 is capable of catalyzing the sulfation of steroid drug compounds such as budesonide and tibolone (Falany et al, 2004; Meloche et al, 2002). In a recent study, SULT2A1 and SULT1A3 displayed the sulfating activities toward buprenorphine and pentazocine, respectively, while several SULTs, particularly SULT1A1, showed strong sulfating activity toward naloxone (Kurogi et al, 2012). …”