TY - JOUR
T1 - Metabolism of thioridazine by microsomal monooxygenases
T2 - Relative roles of p450 and flavin-containing monooxygenase
AU - Blake, B. L.
AU - Rose, R. L.
AU - Mailman, Richard
AU - Levi, P. E.
AU - Hodgson, E.
N1 - Funding Information:
This study was supported in part by NIH Grant ESOOOl 1. We would like to thank Krystyna Tyczkowska for performing the LCMS analysis and Greg Falls for his assistance in purifying mouse liver FMO.
PY - 1995
Y1 - 1995
N2 - 1. The metabolism of thioridazine by the flavin-containing monooxygenase (FMO) of mouse liver and several P450 isozymes was examined using microsomes, purified FMO, and expressed P450 isozymes. Metabolites were identified by hplc. 2. Thermal inactivation and antibodies to NADPH P450 reductase were used to selectively inactivate FMO and P450 respectively. Inactivation of FMO by heat-treatment reduced the formation of thioridazine-N-oxide and northioridazine, whereas inactivation of P450 resulted in decreased amounts of thioridazine-2-sulphoxide, northioridazine, and thioridazine-5-sulphoxide. 3. Liver microsomes from mouse induced with phenobarbital, 3-methylcholanthrene, or acetone were compared with control microsomes. Phenobarbital induction resulted in increased formation of all metabolites except thioridazine-N-oxide, while retaining a general metabolic profile similar to that achieved with control microsomes. Neither 3-methylcholanthrene nor acetone induction had any effect on the in vitro metabolism of thioridazine. 4. FMO purified from mouse liver produced thioridazine-N-oxide as the major metabolite. 5. Preliminary experiments with commercially prepared microsomes made from cells expressing recombinant human liver P450 2D6 and 3A4 suggested that thioridazine is metabolized by 2D6 but not 3A4.
AB - 1. The metabolism of thioridazine by the flavin-containing monooxygenase (FMO) of mouse liver and several P450 isozymes was examined using microsomes, purified FMO, and expressed P450 isozymes. Metabolites were identified by hplc. 2. Thermal inactivation and antibodies to NADPH P450 reductase were used to selectively inactivate FMO and P450 respectively. Inactivation of FMO by heat-treatment reduced the formation of thioridazine-N-oxide and northioridazine, whereas inactivation of P450 resulted in decreased amounts of thioridazine-2-sulphoxide, northioridazine, and thioridazine-5-sulphoxide. 3. Liver microsomes from mouse induced with phenobarbital, 3-methylcholanthrene, or acetone were compared with control microsomes. Phenobarbital induction resulted in increased formation of all metabolites except thioridazine-N-oxide, while retaining a general metabolic profile similar to that achieved with control microsomes. Neither 3-methylcholanthrene nor acetone induction had any effect on the in vitro metabolism of thioridazine. 4. FMO purified from mouse liver produced thioridazine-N-oxide as the major metabolite. 5. Preliminary experiments with commercially prepared microsomes made from cells expressing recombinant human liver P450 2D6 and 3A4 suggested that thioridazine is metabolized by 2D6 but not 3A4.
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U2 - 10.3109/00498259509061859
DO - 10.3109/00498259509061859
M3 - Article
C2 - 7645304
AN - SCOPUS:0029018089
SN - 0049-8254
VL - 25
SP - 377
EP - 393
JO - Xenobiotica
JF - Xenobiotica
IS - 4
ER -