Prevention of butylated hydroxytoluene-induced lung damage in mice by cedar terpene administration

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Abstract

Mice responded to an ip 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, however, if (a) other antioxidants, substituted phenols or BHT metabolites were used rather than BHT itself; (b) mice were under 3 weeks of age; and (c) the mice were exposed to cedar terpenes, either in the form of cedarwood shavings used as cage bedding or by a single ip injection of sesquiterpenoid compounds derived from cedarwood. This prevention of BHT-induced lung damage by the cedar terpenes could not be overcome either by increasing the BHT dose up to 2500 mg/kg, or by delaying terpene administration until 2 hr after the mice had been 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, and 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, either by preventing activation of BHT to an active metabolite, or by accelerating BHT degradation, or both. This is suggested by the observation that immature mice which cannot metabolize drugs to the same extent as adults are naturally resistant to BHT and also by earlier studies which showed induction of drug metabolizing enzymes by cedar terpenes.

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      All mouse strains tested with a single ip. injection of BHT develop acute lung injury characterized by alveolar type 1 cell necrosis followed by alveolar type 2 cell hyperplasia (Adamson, Bowden, Cote, & Witschi, 1977; Malkinson, 1979). However, not all strains are susceptible to the more sub-chronic or chronic effects of BHT as a tumor promoter.

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    Present address: School of Pharmacy, University of Colorado, Boulder, Co. 80309.

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