Interaction of dantrolene with the hepatic mixed function oxidase system

Area of Science:

• Pharmacology
• Hepatology
• Biochemistry

Background:

• The hepatic mixed function oxidase (MFO) system, including cytochrome P450, is crucial for drug metabolism.
• Dantrolene is a muscle relaxant with known effects on cellular processes.
• Understanding drug interactions with hepatic enzymes is vital for predicting toxicity and efficacy.

Purpose of the Study:

• To investigate the impact of dantrolene pretreatment on hepatic MFO system activity and cytochrome P450 content in rats.
• To determine the recovery kinetics of hepatic MFO system activity after dantrolene cessation.
• To elucidate the mechanism underlying dantrolene-induced MFO system inactivation, specifically the role of protein binding.

Main Methods:

• Rats were pretreated with dantrolene (100 mg/kg/day for five days).
• Hepatic MFO system activity and cytochrome P450 content were measured.
• Recovery of MFO activity was monitored for ten days after discontinuing dantrolene.
• The binding of 14C-dantrolene to hepatic proteins (microsomal and soluble) was assessed.
• The influence of phenobarbital and diethylmaleate pretreatment on dantrolene binding was evaluated.

Main Results:

• Dantrolene pretreatment decreased hepatic MFO system activity and cytochrome P450 content by approximately 50%.
• Recovery of MFO activity was slow, with only 63% recovery after ten days, far exceeding dantrolene's half-life (31 minutes).
• 14C-dantrolene formed stable complexes with hepatic microsomal and soluble proteins.
• Phenobarbital pretreatment reduced dantrolene binding, while diethylmaleate enhanced it.

Conclusions:

• Dantrolene causes significant and persistent inactivation of the hepatic MFO system.
• The slow recovery of liver enzyme activity is attributed to the formation of stable dantrolene-protein complexes.
• Dantrolene's interaction with hepatic proteins is modulated by other agents, suggesting complex regulatory mechanisms.