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Vol. 26, Issue 1, 1-4, January 1998
Merck Frosst Center for Therapeutic Research
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: phenacetin O-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 6
-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 vitro
metabolism studies of new chemical entities.
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