Sex and strain differences in response to cocaine

Area of Science:

• Toxicology
• Pharmacology
• Biochemistry

Background:

• Cocaine exposure can cause significant liver damage.
• Sex and genetic background influence drug toxicity.
• Liver microsomal enzymes play a crucial role in drug metabolism and detoxification.

Purpose of the Study:

• To investigate sex and strain differences in cocaine-induced liver injury.
• To determine the role of androgen hormones in these sex differences.
• To explore the involvement of specific liver microsomal enzymes in cocaine toxicity.

Main Methods:

• Administered cocaine to B6AF1 and BALB/cBy mice of different sexes.
• Utilized phenobarbital and pine bedding to induce liver enzyme activity.
• Measured serum glutamic oxaloacetic transaminase (SGOT) levels and observed liver necrosis.
• Assessed the activity of cocaine metabolism enzymes, including cytochrome P-450 and cocaine N-demethylase.

Main Results:

• Female B6AF1 mice exhibited greater SGOT elevation and periportal necrosis after phenobarbital pretreatment compared to males.
• Androgen manipulation (castration, flutamide, testosterone) altered sex-dependent responses.
• Pine bedding induction led to higher SGOT elevations and centrilobular necrosis in male B6AF1 mice.
• BALB/cBy mice showed less cocaine liver damage but higher sensitivity to norcocaine and N-hydroxynorcocaine, linked to lower cocaine N-demethylase activity.

Conclusions:

• Sex and strain differences in cocaine-induced liver damage are modulated by the inducing agent.
• Androgen hormones significantly influence sex-based susceptibility to cocaine hepatotoxicity.
• Liver microsomal enzyme activity, particularly cocaine N-demethylase and N-hydroxylase, is a key determinant of cocaine and its metabolite toxicity.