Received for publication April 13, 2005.
Revised August 4, 2005.
Accepted for publication August 5, 2005.

ESTROUS CYCLE ALTERS NAPHTHALENE METABOLISM IN FEMALE MOUSE AIRWAYS

Abstract

Previous studies have shown variability in naphthalene cytotoxicity, expression of CYP2F2 gene and protein and naphthalene metabolism in random cycling female mice (NIH:Swiss). CYP2F2 metabolizes naphthalene to cytotoxic metabolites in lungs of mice. This study was designed to address the question: Do hormonal changes associated with the estrus cycle alter metabolism of naphthalene in the lung? Adult virgin female mice were manipulated into defined stages of the reproductive cycle: estrus, proestrus and noncycling. Cycling was confirmed by cytology on vaginal swabs. At specific cycle times, extrapulmonary (trachea and bronchi) and intrapulmonary (bronchiolar) conducting airways were microdissected from the lung parenchyma, incubated with naphthalene and the products of naphthalene metabolism were trapped and measured using HPLC. Circulating estradiol levels were measured at necropsy using ELISA. CYP2F2 gene expression was determined by airway level using real time RT PCR and did not vary by estrous cycle stage in intrapulmonary airways but did in extrapulmonary airways. Metabolism of naphthalene varied significantly by estrous cycle stage with the highest level of total metabolism occurring in proestrus (when estrogen is lowest) in intrapulmonary airways. Total activity and metabolite profiles in both extrapulmonary and intrapulmonary airways were affected by cycle stage. We conclude that the hormonal patterns associated with different stages of the estrous cycle 1) alter metabolism of naphthalene in the lungs of mice and 2) alter naphthalene metabolism differentially in extrapulmonary vs intrapulmonary airways.

Key words: cytochrome P450, gender differences, hormonal regulation, inhalation toxicology, lung cancer, lung cytochrome P450, P450 mechanism, pulmonary metabolism, pulmonary toxicology, respiratory toxicants

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