calpain and Lung-Diseases

Previous studies have shown that BHT must be biotransformed, probably to a quinone methide, in order to cause pneumotoxicity in mice. When BHT is incubated with mouse hepatic or pulmonary microsomes, a major metabolite that is formed is the tert-butyl-hydroxylated derivative of BHT (BHT-BuOH). Herein we show that BHT-BuOH has a fourfold greater potency than BHT in increasing the lung wt/body wt ratio, decreases lung cytosolic Ca2+-dependent protease activity at 1/10 the dose required for BHT to do this, and causes pulmonary histopathology at 1/20 the dose of BHT. Lung damage occurs earlier and is repaired faster at lower concentrations of BHT-BuOH than of BHT, but the nature of the damage (type I cell death) and regenerative response (type II cell hyperplasia and differentiation) is apparently identical. Neither BHT-BuOH nor BHT cause damage to liver, kidney, or heart as assessed by light microscopy, so they are both specific pulmonary toxicants. We postulate that BHT-BuOH formation is an essential step in the conversion of BHT to the ultimate pneumotoxin, which might be the corresponding quinone methide.

Topics: Animals; Body Weight; Butylated Hydroxytoluene; Calpain; Dose-Response Relationship, Drug; Hydroquinones; Hydroxylation; Lung; Lung Diseases; Mice; Mice, Inbred C57BL; Organ Size