Abstract
The involvement of FMO in the N-oxygenation of CLZ was investigated by use of purified FMOs and human liver microsomes that contained the mean amount of immunoreactive FMO3 relative to other human liver microsomal preparations in a liver bank. In the microsomal preparation the involvement of FMO was indicated through enzyme inhibition by methimazole, heat inactivation, and protection against heat inactivation by NADPH. Also the Michaelis-Menten kinetic constant;KM determined for CLZ N-oxidation catalyzed by purified human FMO3 (324 μM) was very similar to the mean value obtained in these laboratories for the microsomal preparations of seven human livers.
Footnotes
-
Send reprint requests to: Dr. Edward M. Hawes, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7N 5C9, Canada.
-
Received September 5, 1996; accepted January 24, 1997.
-
This study was supported by the Medical Research Council of Canada, Program Grant PG-11472 (to K.K.M., E.M.H., G.M.). These data were presented in abstract form at the 7th North American ISSX Meeting, held in San Diego, CA, from October 19–24, 1996 [ISSX Proc.10, 221 (1996)].
-
↵2 M. Tugnait et al., unpublished observations.
-
↵3 R. L. Haining, A. P. Hunter, A. J. M. Sadeque, R. M. Philpot, and A. E. Rettie: Baculovirus-mediated expression and purification of human FMO3: catalytic, immunochemical and structural characterization. Drug. Metab. Disp. Submitted for publication.
- Abbreviations used are::
- CLZ
- clozapine
- CYP
- cytochrome P450
- FMO
- flavin-containing monooxygenase
- TCA
- trichloroacetic acid
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|