PT  - JOURNAL ARTICLE
AU  - Jayyosi, Z
AU  - Villoutreix, J
AU  - Ziegler, J M
AU  - Batt, A M
AU  - De Maack, F
AU  - Siest, G
AU  - Thomas, P E
TI  - Identification of cytochrome P-450 isozymes involved in the hydroxylation of dantrolene by rat liver microsomes.
DP  - 1993 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 939--945
VI  - 21
IP  - 5
4099  - http://dmd.aspetjournals.org/content/21/5/939.short
4100  - http://dmd.aspetjournals.org/content/21/5/939.full
SO  - Drug Metab Dispos1993 Sep 01; 21
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.