STRAIN-RELATED DIFFERENCES IN THE PNEUMOTOXIC EFFECTS OF CHRONICALLY ADMINISTERED BUTYLATED HYDROXYTOLUENE ON PROTEIN-KINASE-C AND CALPAIN

BALB/cBy (BALB) and CXB H mice responded similarly to a single intrape ritoneal injection of butylated hydroxytoluene (BHT). This transient p neumotoxicity was characterized by an elevated lung weight and alveola r damage. These changes were accompanied by alterations in the calcium second messenger pathway, namely, two- to five-fold decreases in the activities and pulmonary content of protein kinase C alpha (PKC alpha) and calcium-dependent protease isozyme II (calpain II). BALB and CXB H mice varied in their responsiveness to a chronic (4-6 weekly injecti ons) BHT regimen. CXB H mice became tolerant to BHT and all of the abo ve parameters had returned to control values when examined after the l ast injection. Chronic BHT administration also failed to enhance lung tumor multiplicity in CXB H mice when the first BHT injection was prec eded by the carcinogen, urethane. In contrast, the additional BHT dose s potentiated the pathological and biochemical alterations in BALB mic e above that found with acute treatment. This included a chronic infla mmatory response characterized by the presence of activated macrophage s, and a lung tumor multiplicity that was 3-fold greater than in BALB mice receiving urethane alone. One BHT injection increased calpain II mRNA in both strains (1.5- to 3-fold); mRNA declined following multipl e BHT injections in BALB mice, but remained elevated in CXB H mice. St udies with the cytochrome P450 inhibitor, piperonyl butoxide, indicate d that metabolism of BHT was required for both its acute and chronic e ffects. We conclude the following: (i) Differences between inbred mice in their susceptibility to chronic pneumotoxicant exposure may exist even when they respond similarly to an acute exposure of the same agen t; (ii) A chronic inflammatory state involving a high concentration of activated macrophages may play an important role in tumor enhancement by a non-carcinogen; (iii) The protein contents of PKC alpha and calp ain II decrease during BHT-induced lung damage.