RT Journal Article
SR Electronic
T1 Identification of cytochrome P-450 isozymes involved in the hydroxylation of dantrolene by rat liver microsomes.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 939
OP 945
VO 21
IS 5
A1 Z Jayyosi
A1 J Villoutreix
A1 J M Ziegler
A1 A M Batt
A1 F De Maack
A1 G Siest
A1 P E Thomas
YR 1993
UL http://dmd.aspetjournals.org/content/21/5/939.abstract
AB The role of individual rat liver cytochrome P-450 isozymes in the metabolism of the skeletal muscle relaxant, dantrolene, was studied. Following incubation of dantrolene with hepatic microsomes from 3-methylcholanthrene-treated rats, two major hydroxylated metabolites were identified. Using inhibitory antibodies specific for individual cytochrome P-450 isozymes, cytochromes P-450 1A1, 1A2, and 3A were identified to be involved in dantrolene hydroxylations. In liver microsomes from 3-methylcholanthrene-treated rats, antibodies specific for cytochrome P-450 1A1 and 1A2 inhibited hydroxylation of dantrolene by 60% and 20%, respectively. Kinetics studies using these microsomes showed that dantrolene hydroxylation was biphasic with a low KM (0.06-0.08 microM) and high KM (5-7 microM). Cytochrome P-450 1A1 was responsible for the low KM hydroxylation of dantrolene, whereas cytochrome P-450 1A2 was responsible for the high KM. In hepatic microsomes from pregnenolone-16 alpha-carbonitrile-treated rats, an antibody specific for cytochrome P-450 3A completely inhibited the formation of 5-hydroxydantrolene, the major metabolite formed by these microsomes.