title: Estrogen metabolism within the lung and its modulation by tobacco smoke.
abstract: Although estrogen and the enzymes responsible for its metabolism have been detected within the lung, the ability of this tissue to metabolize estrogen has not been demonstrated previously. The goal of this study was to characterize the profile of estrogen metabolites within the murine lung and to determine the effect of tobacco smoke exposure on metabolite levels. Use of liquid chromatography-tandem mass spectrometry led to the detection of three estrogens (E1, E2 and E3) and five estrogen metabolites (2-OHE1, 4-OHE1, 4-OHE2, 2-OMeE1 and 2-OMeE2) within the perfused lung, with 4-OHE1 being the most abundant species. Levels of 4-OHEs, carcinogenic derivatives produced primarily by cytochrome P450 1B1 (Cyp1b1), were 2-fold higher in females than males. Deletion of Cyp1b1 in females led to a dramatic reduction (21-fold) in 4-OHEs, whereas levels of 2-OHE1 and the putative protective estrogen metabolite 2-OMeE2 were increased (2.4- and 5.0-fold, respectively) (P = 0.01). Similar quantitative differences in estrogen metabolite levels were observed between Cyp1b1 null and wild-type males. Exposure of female mice to tobacco smoke for 8 weeks (2h per day, 5 days per week) increased the levels of 4-OHE1 (4-fold) and 2-OHE2 (2-fold) within the lung while reducing the total concentration of 2-OMeEs to 70% of those of unexposed controls. These data suggest that tobacco smoke accelerates the production of 4-OHEs within the lung; carcinogenic metabolites that could potentially contribute to lung tumor development. Thus, inhibition of CYP1B1 may represent a promising strategy for the prevention and treatment of lung cancer.
authors.affiliation: Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mace
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Vanderveer
authors.forename: Laura R
authors.initials: LR
authors.lastname: Workman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Slifker
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005838:Genotype; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012737:Sex Factors; D012906:Smoke
chemical_list: D004967:Estrogens; D012906:Smoke; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D002394:Catechol O-Methyltransferase