title: 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.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Seattle, Washington, USA. ldickman@amgen.com
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Dickmann
authors.forename: Brooke M
authors.initials: BM
authors.lastname: VandenBrink
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
mesh_terms: D045784:Abietanes / Q000009:adverse effects / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D010936:Plant Extracts / Q000009:adverse effects / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects
chemical_list: D045784:Abietanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D010936:Plant Extracts; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; C018381:salvin; D012293:Rifampin