Metabolism of [D10]phenanthrene to tetraols in smokers for potential lung cancer susceptibility assessment: comparison of oral and inhalation routes of administration.
Author(s): Zhong Y, Wang J, Carmella SG, Hochalter JB, Rauch D, Oliver A, Jensen J, Hatsukami DK, Upadhyaya P, Zimmerman C, Hecht SS
Affiliation(s): Departments of Pharmacology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Publication date & source: 2011-07, J Pharmacol Exp Ther., 338(1):353-61. Epub 2011 Apr 22.
Publication type: Comparative Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural
Polycyclic aromatic hydrocarbons (PAHs) are believed to be among the causative agents for lung cancer in smokers. PAHs require metabolic activation for carcinogenicity. One pathway produces diol epoxides that react with DNA, causing mutations. Because diol epoxides are converted to tetraols, quantitation of tetraols can potentially be used to identify smokers who may be at higher risk for lung cancer. Our approach uses [D(10)]phenanthrene, a labeled version of phenanthrene, a noncarcinogenic PAH structurally analogous to carcinogenic PAH. Although smokers are exposed to PAH by inhalation, oral dosing would be more practical for phenotyping studies. Therefore, we investigated [D(10)]phenanthrene metabolism in smokers after administration by inhalation in cigarette smoke or orally. Sixteen smokers received 10 mug of [D(10)]phenanthrene in a cigarette or orally. Plasma and urine samples were analyzed for [D(10)]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D(10)]PheT), the major end product of the diol epoxide pathway, by gas chromatography-negative ion chemical ionization-tandem mass spectrometry. The ratios of [D(10)]PheT (oral dosing/inhalation) in 15 smokers were 1.03 +/- 0.32 and 1.02 +/- 0.35, based on plasma area under the concentration-time curve (0-infinity) and total 48-h urinary excretion, respectively. Overall, there was no significant difference in the extent of [D(10)]PheT formation after the two different routes of exposure in smokers. A large interindividual variation in [D(10)]PheT formation was observed. These results demonstrate that the level of [D(10)]PheT in urine after oral dosing of [D(10)]phenanthrene can be used to assess individual capacity of PAH metabolism by the diol epoxide pathway.