Project: Research project

Project Details


Extrapolation of toxicologic data derived in animals to the human is a
complex task that is especially difficult with those agents where there are
marked species differences in the response and where there is a lack of
epidemiologic data. There are a number of volatile industrial and
environmental chemicals including naphthalene, dichloroethylene and
trichloroethylene that result in dose-dependent necrosis of the pulmonary
Clara cells of the mouse but in no injury to rat or hamster lung.
Naphthalene-induced lung injury depends upon cytochrome P450 mediated
metabolism and correlates with the glutathione (GSH) depletion and covalent
binding by reactive metabolites to pulmonary macromolecules. However,
covalent binding in nontarget tissues was higher than in the lung
suggesting that then nature of reactive, potentially cytotoxic metabolites
differed. Subsequent examination of the microsomal metabolism of
naphthalene has demonstrated an excellent correlation between the formation
of a particular reactive metabolite (trapped as a GSH adduct) and the
species/organo-selectivity in naphthalene-induced cytotoxicity. These
studies propose to determine whether urinary mercapturic acids derived from
these GSH adducts can be used as a probe to examine the activity and
metabolic selectivity of the pulmonary monooxygenase system. The
importance stems from the fact that in vitro studies of human lung P450
xenobiotic metabolism have consistently failed to demonstrate significant
activity possible because of artifacts introduced during tissue
preparation. The goal of these studies is to provide a means to examine
interindividual variations in activity and selectivity of the human lung
monooxygenases. The proposed studies will develop methods for the
extraction and HPLC separation and quantitation of urinary naphthalene
mercapturates. Each of the isomeric GSH adducts will be administered to
animals to determine their metabolic fate. The excretion of each of the
isomers will be monitored in both rats and mice exposed to naphthalene by
inhalation and by ip injection to determine whether the rates of excretion
of the isomers are dependent upon the first pass organ (liver or lung) and
the species exposed.
Effective start/end date5/5/864/30/88


  • National Institutes of Health
  • National Institutes of Health


  • Environmental Science(all)
  • Medicine(all)


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