Cortisol metabolism in vitro--II. Species difference

Area of Science:

• Pharmacology
• Biochemistry
• Toxicology

Background:

• Cortisol 6 beta-hydroxylase activity is proposed as a specific marker for cytochrome P4503A (CYP3A) in the liver.
• Previous research indicated complex and variable cortisol metabolism in human liver fractions, necessitating comprehensive metabolite analysis for accurate CYP3A activity assessment.

Purpose of the Study:

• To define and compare the metabolism of [3H]cortisol in hepatic microsomes from various animal species and rat cytosol with human liver microsomes.
• To evaluate the suitability of animal models for studying CYP3A-mediated cortisol metabolism.

Main Methods:

• Metabolite characterization using co-chromatography with authentic standards, mass spectrometry, and radiometric High-Performance Liquid Chromatography (HPLC).
• Incubation of [3H]cortisol with hepatic microsomes from rats, guinea pigs, hamsters, and mice, as well as rat cytosol.
• Comparison of metabolic profiles with those obtained from human liver microsomes.

Main Results:

• All tested animal species' microsomes metabolized cortisol, but with quantitatively and qualitatively different profiles compared to humans.
• Animal microsomal metabolic profiles were generally simpler; hamsters, mice, and guinea pigs exhibited only 6 beta-hydroxylase and 11 beta-dehydrogenase activity.
• Female rats displayed the most complex microsomal metabolism, including A-ring reduction, and produced two unique metabolites not found in humans. Male rat cytosol primarily produced 20 beta-dihydrocortisone, while female rat cytosol mirrored human cytosol products.

Conclusions:

• Hepatic cortisol metabolism exhibits significant interspecies variability.
• The hamster presents the simplest model for investigating cortisol 6 beta-hydroxylase activity due to its limited metabolic pathways.
• The complexity and variability of cortisol metabolism across species highlight challenges in using it as a universal CYP3A activity marker.