Evidence for a role of tert-butyl hydroxylation in the induction of pneumotoxicity in mice by butylated hydroxytoluene.
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.
Malkinson
A M
AM
Molecular and Environmental Toxicology Program, School of Pharmacy, University of Colorado, Boulder 80309-0297.
Thaete
L G
LG
Blumenthal
E J
EJ
Thompson
J A
JA
D000818:Animals; D001835:Body Weight; D002084:Butylated Hydroxytoluene / Q000378:metabolism / Q000633:toxicity*; D002154:Calpain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006873:Hydroquinones / Q000378:metabolism; D006900:Hydroxylation; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects
D006873:Hydroquinones; D002084:Butylated Hydroxytoluene; D002154:Calpain