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 intraperitoneal injection of butylated hydroxytoluene (BHT). This transient pneumotoxicity was characterized by an elevated lung weight and alveolar 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 injections) BHT regimen. CXB H mice became tolerant to BHT and all of the above parameters had returned to control values when examined after the last injection. Chronic BHT administration also failed to enhance lung tumor multiplicity in CXB H mice when the first BHT injection was preceded by the carcinogen, urethane. In contrast, the additional BHT doses potentiated the pathological and biochemical alterations in BALB mice above that found with acute treatment. This included a chronic inflammatory response characterized by the presence of activated macrophages, 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 multiple BHT injections in BALB mice, but remained elevated in CXB H mice. Studies with the cytochrome P450 inhibitor, piperonyl butoxide, indicated that metabolism of BHT was required for both its acute and chronic effects. 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 agent; (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 calpain II decrease during BHT-induced lung damage.
Miller
A C
AC
Molecular Toxicology Program, School of Pharmacy, University of Colorado, Denver 80262.
Dwyer
L D
LD
Auerbach
C E
CE
Miley
F B
FB
Dinsdale
D
D
Malkinson
A M
AM
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002084:Butylated Hydroxytoluene / Q000633:toxicity*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D010882:Piperonyl Butoxide / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D013045:Species Specificity
D012333:RNA, Messenger; D002084:Butylated Hydroxytoluene; D011493:Protein Kinase C; D002154:Calpain; D010882:Piperonyl Butoxide