Hepatotoxicity of germander in mice.
OBJECTIVE
An epidemic of hepatitis due to germander teas or capsules recently occurred in France. The aim of the present study was to show the hepatotoxicity of germander and determine its mechanism in mice.


METHODS
A germander tea lyophilisate and a fraction that isolated and concentrated 10-fold the furano neo-clerodane diterpenoids of the lyophilisate were prepared.


RESULTS
(1) Intragastric administration of the lyophilisate (1.25 g/kg) or the furano neo-clerodane diterpenoid fraction (0.125 mg/kg) produced similar midzonal liver cell necrosis at 24 hours in mice. (2) Toxicity was prevented by pretreatment with a single dose of troleandomycin (a specific inhibitor of cytochromes P4503A) and enhanced by pretreatment with dexamethasone or clotrimazole (two inducers of cytochromes P4503A). (3) Toxicity was attenuated by pretreatment with butylated hydroxyanisole or clofibrate (two inducers of microsomal epoxide hydrolase) and markedly increased by phorone-induced glutathione depletion.


CONCLUSIONS
We conclude that germander constituents (probably its furano neo-clerodane diterpenoids) are transformed by cytochromes P450 (particularly P4503A) into hepatotoxic metabolites. The metabolites (probably epoxides) are partly inactivated by glutathione and probably epoxide hydrolase.
Loeper
J
J
Institut National de la Santé et de la Recherche Médicale U24, Clichy, France.
Descatoire
V
V
Letteron
P
P
Moulis
C
C
Degott
C
C
Dansette
P
P
Fau
D
D
Pessayre
D
D
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001628:Beverages / Q000009:adverse effects*; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004224:Diterpenes / Q000633:toxicity; D004851:Epoxide Hydrolases / Q000502:physiology; D005978:Glutathione / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008517:Phytotherapy; D010946:Plants, Medicinal; D014217:Troleandomycin / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004224:Diterpenes; D014217:Troleandomycin; D000410:Alanine Transaminase; D004851:Epoxide Hydrolases; D005978:Glutathione