In vitro hepatotoxicity and cytochrome P450 induction and inhibition characteristics of carnosic acid, a dietary supplement with antiadipogenic properties.

Abstract

Carnosic acid is a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), which may have anticancer, antiadipogenic, and anti-inflammatory properties. Recently, carnosic acid was shown to prevent weight gain and hepatic steatosis in a mouse model of obesity and type II diabetes. Based on these results, carnosic acid has been suggested as a potential treatment for obesity and nonalcoholic fatty liver disease; however, little is known about the safety of carnosic acid at doses needed to elicit a pharmacological effect. For this reason, hepatotoxicity and cytochrome P450 inhibition and induction studies were performed in primary human hepatocytes and microsomes. Measuring cellular ATP, carnosic acid showed a dose-dependent increase in hepatotoxicity with an EC(50) value of 94.8 ± 36.7 μM in three human hepatocyte donors without a concurrent increase in the apoptosis markers caspase-3/7. In human liver microsomes, carnosic acid did not exhibit significant time-dependent inhibition for any of the cytochrome P450 enzymes investigated, although it did inhibit CYP2C9- and CYP3A4-catalyzed reactions with K(i) values of 9.2 and 4.3 μM, respectively. Carnosic acid also induced CYP2B6 and CYP3A4 mRNA and enzyme activity in a dose-dependent manner. At 10 μM, carnosic acid increased CYP2B6 enzyme activity 61.6 and 49.3% in two donors compared with phenobarbital, and it increased CYP3A enzyme activity 82.6 and 142% compared with rifampicin. These results indicate the potential for drug interactions with carnosic acid and illustrate the need for an appropriate safety assessment before being used as a weight loss supplement.

• Authors: Leslie J Dickmann, Brooke M VandenBrink, Yvonne S Lin
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 40 Issue 7 Pg. 1263-7 (Jul 2012) ISSN: 1521-009X [Electronic] United States
• PMID: 22531045 (Publication Type: Journal Article)

Chemical References

• Abietanes
• Cytochrome P-450 Enzyme Inhibitors
• Plant Extracts
• Adenosine Triphosphate
• Cytochrome P-450 Enzyme System
• salvin
• Rifampin

Topics

• Abietanes (adverse effects, pharmacology)
• Adenosine Triphosphate (metabolism)
• Adipogenesis (drug effects)
• Cells, Cultured
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (metabolism)
• Dietary Supplements
• Dose-Response Relationship, Drug
• Drug Interactions
• Hepatocytes (drug effects, enzymology, metabolism)
• Humans
• Microsomes, Liver (drug effects, enzymology, metabolism)
• Plant Extracts (adverse effects, pharmacology)
• Rifampin (pharmacology)
• Weight Loss (drug effects)