HEPATOTOXICITY OF GERMANDER (TEUCRIUM-CHAMAEDRYS L) AND ONE OF ITS CONSTITUENT NEOCLERODANE DITERPENES TEUCRIN-A IN THE MOUSE

The hepatotoxicity of the herbal plant germander and that of one of it s major furanoneoclerodane diterpenes, teucrin A, were investigated in mice. Teucrin A was found to cause the same midzonal hepatic necrosis as observed with extracts of the powdered plant material. Evidence th at bioactivation of teucrin A by cytochromes P450 (P450) to a reactive metabolite(s) is required for initiation of the hepatocellular damage is provided by results of experiments on the induction and inhibition of P450 and from studies on the effects of glutathione depletion. Pre treatment of mice with the P450 inducer phenobarbital enhanced the hep atotoxic response, as indicated by an increase in plasma alanine amino transferase (ALT) levels and hepatic necrosis, while pretreatment with the P450 inhibitor piperonyl butoxide markedly attenuated the toxic r esponse. Hepatotoxicity of teucrin A also was increased following pret reatment with the inhibitor of glutathione synthesis buthionine sulfox imine. Most importantly, the tetrahydrofuran analog of teucrin A, obta ined by selective chemical reduction of the furan ring, was not hepato toxic, a result that provides strong evidence that oxidation of the fu ran ring moiety of the neoclerodane diterpenes is involved in the init iation of hepatocellular injury caused by germander.