Abstract
In this study, we report the effect of methanol, dimethyl sulfoxide (DMSO), and acetonitrile on the cytochrome P450 (P450)-mediated metabolism of several substrates in human liver microsomes: phenacetinO-deethylation for P4501A2, coumarin 7-hydroxylation for P4502A6, tolbutamide hydroxylation for P4502C8/2C9,S-mephenytoin 4′-hydroxylation for P4502C19, dextromethorphan O-demethylation for P4502D6, chlorzoxazone 6-hydroxylation for P4502E1, and testosterone 6β-hydroxylation for P4503A4. DMSO was found to inhibit several P450-mediated reactions (2C8/2C9, 2C19, 2E1, and 3A4) even at low concentrations (0.2%). There was no measurable effect on the catalytic activity of the various P450s when methanol was present at levels ≤1%, except for P4502C8/9 and 2E1. Acetonitrile did not noticeably change the catalytic activity of the P4502C8/2C9, 2C19, 2D6, and 2E1 enzymes at concentrations ≤1%. It was found that the content level of the organic solvents should be kept lower than 1% because, for all three solvents, a concentration of 5% strongly affected the metabolism of the various probes. These findings should be taken into consideration when designing in vitrometabolism studies of new chemical entities.
Footnotes
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Send reprint requests to: Nathalie Chauret, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire Dorval, Quebec H9R 4P8, Canada.
- Abbreviations used are::
- P450
- cytochrome P450
- DMSO
- dimethyl sulfoxide
- Received August 28, 1997.
- Accepted October 14, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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