Metabolism of thioridazine by microsomal monooxygenases: Relative roles of P450 and flavin-containing monooxygenase

Article abstract of DOI:10.3109/00498259509061859

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. 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. 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. FMO purified from mouse liver produced thioridazine-N-oxide as the major metabolite. 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.

Full text of DOI:10.3109/00498259509061859

Xenobiotica
the fate of foreign compounds in biological systems
ISSN: 0049-8254 (Print) 1366-5928 (Online) Journal homepage: http://www.tandfonline.com/loi/ixen20
Metabolism of thioridazine by microsomal
monooxygenases: relative roles of P450 and flavin-
containing monooxygenase
B. L. Blake, R. L. Rose, R. B. Mailman, P. E. Levi & E. Hodgson
To cite this article: B. L. Blake, R. L. Rose, R. B. Mailman, P. E. Levi & E. Hodgson (1995)
Metabolism of thioridazine by microsomal monooxygenases: relative roles of P450 and flavin-
containing monooxygenase, Xenobiotica, 25:4, 377-393
To link to this article: http://dx.doi.org/10.3109/00498259509061859
Published online: 22 Sep 2008.
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Date: 21 September 2015, At: 02:04