PREVENTION OF BUTYLATED HYDROXYTOLUENE-INDUCED LUNG DAMAGE IN MICE BY CEDAR TERPENE ADMINISTRATION

Mice responded to an i.p. injection of 400 mg/kg butylated hydroxytoluene (BHT) with a loss of body weight and a rise in lung weight characterized by increases in cellularity, rate of thymidine incorporation into DNA and total lung DNA content. These responses did not occur if other antioxidants, substituted phenols or BHT metabolites were used rather than BHT itself; if mice were under 3 wk of age or if the mice were exposed to cedar terpenes in the form of cedarwood shavings used as cage bedding or by a single i.p. injection of sesquiterpenoid compounds compounds derived from cedarwood. This prevention of BHT-induced lung damage by the cedar terpenes could not be overcome by increasing the BHT dose up to 2500 mg/kg or by delaying terpene administration until 2 h after the mice were injected with BHT. The resistance conferred by the terpenes was fully reversible within 4 days after removal of the terpenes from the mice. The lung weights in each of 13 different inbred strains of mice were increased by BHT; this increase could be prevented by cedar terpene administration. The mechanism(s) by which the terpenes prevent BHT toxicity is/are unknown. The terpenes may act at the level of BHT metabolism by preventing activation of BHT to an active metabolite or by accelerating BHT degradation or both. Immature mice which cannot metabolize drugs to the same extent as adults are naturally resistant to BHT. Induction of drug metabolizing enzymes by cedar terpenes was demonstrated earlier.