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Vol. 27, Issue 2, 246-249, February 1999
Gentest Corporation, Woburn, Massachusetts
The effects of methanol, ethanol, dimethyl sulfoxide (DMSO), and
acetonitrile were studied in vitro on nine individual,
cDNAexpressed cytochrome P-450 activities (phenacetin
O-deethylase for CYP1A1 and CYP1A2, coumarin
7-hydroxylase for CYP2A6, testosterone 6
-hydroxylase for CYP3A4,
7-ethoxy-4-trifluoromethylcoumarin deethylase for CYP2B6, paclitaxel
6
-hydroxylase for CYP2C8, diclofenac 4'-hydroxylase for CYP2C9,
S-mephenytoin 4-hydroxylase for CYP2C19, and
(±)-bufuralol 1'-hydroxylase for CYP2D6) in commercially available
human lymphoblastoid microsomes. These data show that specific solvents
have enzyme-selective effects on P-450 activities. Methanol did not
substantially inhibit (
10%) any of the activities at 0.3%, but did
inhibit CYP1A1, CYP2B6, CYP2C9, and CYP2D6 by 12 to 26% at 1%. In
contrast, 0.1% ethanol inhibited CYP1A1, CYP2B6, and CYP2C19 by 20 to
30%. Ethanol at 1% did not inhibit CYP1A2, CYP3A4, CYP2C8, and
CYP2C9. DMSO inhibited CYP3A4, CYP2C19, and CYP2D6 by 15 to 25% at
0.1%. However, DMSO had little effect on CYP1A2, CYP2A6, and CYP2C8.
Acetonitrile, like methanol, did not inhibit any P-450 activity at
0.3% solvent except for CYP1A1 (26%) and CYP2B6 (13%). At 1%,
acetonitrile decreased activities of CYP1A1 and CYP2B6 by 40 to 60%,
and inhibited CYP2A6, CYP3A4, CYP2C19, and CYP2D6 activity by 10 to
20%. Acetonitrile also increased CYP2C9 activity by 10 to 15% above
control values at 1 to 3% solvent. Excluding solubility
considerations, methanol and acetonitrile appear to be the most
suitable solvents for the introduction of substances to cytochrome
P-450 incubations for in vitro metabolism studies.
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