RT Journal Article
SR Electronic
T1 Effects of Organic Solvents on the Activities of Cytochrome P450 Isoforms, UDP-Dependent Glucuronyl Transferase, and Phenol Sulfotransferase in Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 141
OP 144
VO 29
IS 2
A1 Easterbrook, Judy
A1 Lu, Chuang
A1 Sakai, Yumiko
A1 Li, Albert P.
YR 2001
UL http://dmd.aspetjournals.org/content/29/2/141.abstract
AB We studied the effects of acetonitrile, dimethyl sulfoxide (DMSO), and methanol (MeOH) in human hepatocytes on cytochrome P450 (CYP) and phase II conjugation activities: phenacetinO-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), tolbutamide 4-hydroxylation (CYP2C9),S-mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), testosterone 6β-hydroxylation (CYP3A4), and umbelliferone glucuronidation and sulfation. The solvents were evaluated at concentrations (v/v) of 0.1, 1, and 2%. Previously cryopreserved human hepatocytes pooled from multiple donors were used as suspension cultures in this study. DMSO was found to inhibit CYP2C9 and CYP2C19, CYP2E1, and CYP3A4 in a concentration-dependent manner. At 2% DMSO, the activities for the four isoforms were approximately 40% (CYP2C9), 23% (CYP2C19), and 11% (CYP2E1) of that observed for 0.1% acetonitrile and 45% (CYP3A4) of that observed for 1% acetonitrile. No apparent inhibitory effects were observed for the other activities evaluated. Methanol was found to inhibit CYP2C9 and CYP2E1 activities, but to a lesser extent than DMSO. Acetonitrile had no apparent effects on any of the on any of the activities evaluated. These findings should be considered when choosing an organic solvent for metabolism studies with human hepatocytes. The American Society for Pharmacology and Experimental Therapeutics