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 [35S]sulfate in the presence of each of the three opioid drugs, showed
the generation and release of their [35S]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.