TY - JOUR 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 SP - 939 LP - 945 VL - 21 IS - 5 AU - Z Jayyosi AU - J Villoutreix AU - J M Ziegler AU - A M Batt AU - F De Maack AU - G Siest AU - P E Thomas Y1 - 1993/09/01 UR - http://dmd.aspetjournals.org/content/21/5/939.abstract N2 - 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. ER -