Hepatotoxicity of germander in mice

doi:10.1016/0016-5085(94)90606-8

Gastroenterology

Volume 106, Issue 2, February 1994, Pages 464-472

https://doi.org/10.1016/0016-5085(94)90606-8 Get rights and content

Abstract

Background/Aims: 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.

References (51)

N Mostefa-Kara et al.
Fatal hepatitis after herbal tea
Lancet
(1992)
G Savona et al.
Dihydroteugin, a neoclerodane diterpenoid from Teucrium chamaedris
Phytochemistry
(1982)
M-C Rodriguez et al.
Neo-clerodane diterpenoids from Teucrium chamaedris: the identity of teucrin B with dihydroteugin
Phytochemistry
(1984)
PL Koser et al.
The genetics of aflatoxin B₁ metabolism. Association of the induction of aflatoxin B₁-4-hydroxylase with the transcriptional activation of cytochrome P₃-450 gene
J Biol Chem
(1988)
HS Ramsdell et al.
Bioactivation of aflatoxin B₁ by human liver microsomes. Role of cytochrome P450 IIIA enzymes
Toxicol Appl Pharmacol
(1991)
KM Madyastha et al.
Pulegone mediated hepatotoxicity: evidence for covalent binding of R(+)-[¹⁴C]pulegone to microsomal proteins in vitro
Chem-Biol Interac
(1989)
A Chatterjee et al.
Isocrautocaudin, a new nor clerodane-type diterpene from Croton caudatus
Phytochemistry
(1978)
GL Ellman
Tissue sulphydryl groups
Arch Biochem Biophys
(1959)
OH Lowry et al.
Protein measurement with the Folin phenol reagent
J Biol Chem
(1951)
T Omura et al.
The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature
J Biol Chem
(1964)

M Murray

Complexation of cytochrome P-450 isoenzymes in hepatic microsomes from SKF 525-A-induced rats

Arch Biochem Biophys

(1988)

D Larrey et al.

Metabolic activation of the new tricyclic anti-depressant tianeptine by human liver cytochrome P-450

Biochem Pharmacol

(1990)

T Yanagimoto et al.

Mouse liver cytochrome P-450 (P-450IIIAM1): its cDNA cloning and inducibility by dexamethasone

Biochim Biophys Acta

(1992)

J Traber et al.

In vivo modulation of total and mitochondrial glutathione in rat liver. Depletion by phorone and rescue by N-acetylcysteine

Biochem Pharmacol

(1992)

BD Hammock et al.

Differential induction of cytosolic epoxide hydrolase, microsomal epoxide hydrolase, and glutathione S-transferase activities

Toxicol Appl Pharmacol

(1983)

TM Guenthner

Selective inhibition and selective induction of multiple microsomal epoxide hydrolases

Biochem Pharmacol

(1986)

P Bentley et al.

Immunochemical evidence of epoxide hydratase in rat liver: effects of 2-acetyl-aminofluorene

Biochem Biophys Res Commun

(1979)

D Pessayre et al.

Effect of fasting on metabolite-mediated hepatotoxicity in the rat

Gastroenterology

(1979)

J Loeper et al.

Cytochromes P-450 in human hepatocyte plasma membrane: recognition by several autoantibodies

Gastroenterology

(1993)

N Bach et al.

Comfrey herb tea-induced hepatic veno-occlusive disease

Am J Med

(1989)

U Beuers et al.

Hepatitis after chronic abuse of senna

Lancet

(1991)

A Castot et al.

Hépatites observées au cours d'un traitement par un médicament ou une tisane contenant de la Germandrée petit-chêne. Bilan des 26 cas rapportés aux Centres Régionaux de Pharmacovigilance

Gastroenterol Clin Biol

(1992)

D Larrey et al.

Hepatitis after germander (Teucrium chamaedris) administration: another instance of herbal medicine hepatotoxicity

Ann Intern Med

(1992)

F Piozzi et al.

Advances in the chemistry of the furanoditerpenoids from Teucrium species

Heterocycles

(1987)

JR Mitchell et al.

Hepatic necrosis caused by furosemide

Nature

(1974)

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: Supported in part by a grant from the Ministère de la Santé et de l'Action Humanitaire (Direction de la Pharmacie et du Médicament).

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Hepatotoxicity of germander in mice

Abstract

Lancet

Phytochemistry

Phytochemistry

J Biol Chem

Toxicol Appl Pharmacol

Chem-Biol Interac

Phytochemistry

Arch Biochem Biophys

J Biol Chem

J Biol Chem

Arch Biochem Biophys

Biochem Pharmacol

Biochim Biophys Acta

Biochem Pharmacol

Toxicol Appl Pharmacol

Biochem Pharmacol

Biochem Biophys Res Commun

Gastroenterology

Gastroenterology

Am J Med

Lancet

Hépatites observées au cours d'un traitement par un médicament ou une tisane contenant de la Germandrée petit-chêne. Bilan des 26 cas rapportés aux Centres Régionaux de Pharmacovigilance

Gastroenterol Clin Biol

Hepatitis after germander (Teucrium chamaedris) administration: another instance of herbal medicine hepatotoxicity

Ann Intern Med

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Nature