TY - JOUR T1 - Comparison of Human Liver and Small Intestinal Glutathione <em>S</em>-Transferase-Catalyzed Busulfan Conjugation <em>in Vitro</em> JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 52 LP - 55 VL - 26 IS - 1 AU - John P. Gibbs AU - Ji-Sun Yang AU - John T. Slattery Y1 - 1998/01/01 UR - http://dmd.aspetjournals.org/content/26/1/52.abstract N2 - The apparent oral clearance of busulfan has been observed to vary as much as 10-fold in the population of children and adults receiving high-dose busulfan. The only identified elimination pathway for busulfan involves glutathione conjugation. The reaction is predominantly catalyzed by glutathione S-transferase (GST) A1-1, which is present in both liver and intestine. The purpose of this study was to compare busulfanVmax/Km in cytosol prepared from adult human liver and small intestine. Tetrahydrothiophenium ion formation rate per milligram of cytosolic protein was constant along the length (assessed in 30-cm segments) of three individual small intestines. A 30-cm-long intestinal segment 90–180 cm from the pylorus was chosen to be representative of intestinal cytosolic busulfan conjugating activity. BusulfanVmax/Km (mean ± SD) in cytosol prepared from 23 livers and 12 small intestines was 0.166 ± 0.066 and 0.176 ± 0.085 μl/min/mg cytosolic protein, respectively, in incubations with 5 μM busulfan, 1 mM glutathione, and 2 mg of cytosolic protein. The relative content of GSTα (A1-1, A1-2, and A2-2) was compared for human liver and intestinal cytosol using Western blot. The levels of GSTα in liver and intestinal cytosol were 1.12 ± 0.56 and 1.36 ± 0.32 integrated optimal density units/5 μg cytosolic protein, respectively. Busulfan conjugation in vitro was comparable per milligram of cytosolic protein in liver and intestinal cytosol. The American Society for Pharmacology and Experimental Therapeutics ER -