Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes.

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Easterbrook J, Lu C, Sakai Y, Li AP

Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes.

Drug Metab Dispos. 2001 Feb;29(2):141-4.

PubMed ID

11159803 [ View in PubMed

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Abstract

We studied the effects of acetonitrile, dimethyl sulfoxide (DMSO), and methanol (MeOH) in human hepatocytes on cytochrome P450 (CYP) and phase II conjugation activities: phenacetin O-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), tolbutamide 4-hydroxylation (CYP2C9), S-mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), testosterone 6beta-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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dimethyl sulfoxide	Cytochrome P450 2C19	Protein	Humans	Unknown	Inhibitor	Details