TY - JOUR
T1 - Immediate consequences of cigarette smoking
T2 - Rapid formation of polycyclic aromatic hydrocarbon diol epoxides
AU - Zhong, Yan
AU - Carmella, Steven G.
AU - Upadhyaya, Pramod
AU - Hochalter, J. Bradley
AU - Rauch, Diane
AU - Oliver, Andrew
AU - Jensen, Joni
AU - Hatsukami, Dorothy
AU - Wang, Jing
AU - Zimmerman, Cheryl
AU - Hecht, Stephen S.
PY - 2011/2/18
Y1 - 2011/2/18
N2 - Polycyclic aromatic hydrocarbons (PAH) are among the likely major causative agents for lung cancer in smokers. PAH require metabolic activation to exert their carcinogenic effects, and one important pathway proceeds through a three-step sequence resulting in the formation of diol epoxides, which react with DNA to produce adducts that can cause mutations and initiate the carcinogenic process. However, no previous published studies have examined this critical pathway in humans specifically exposed to PAH by inhalation of cigarette smoke. This study used a unique approach employing a stable isotope derivative of phenanthrene, the simplest PAH with a bay region, a feature closely associated with PAH carcinogenicity. Twelve subjects each smoked a cigarette to which [D10]phenanthrene had been added. Plasma was analyzed for [D10]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4- tetrahydrophenanthrene ([D10]PheT), the major end product of the diol epoxide metabolism pathway of phenanthrene. The analysis was performed by gas chromatography-negative ion chemical ionization-tandem mass spectrometry, using [13C6]PheT as internal standard. The results demonstrated that the three-step pathway resulting in the formation of diol epoxides, as monitored by [D10]PheT, occurred with remarkable rapidity. Levels of [D10]PheT in plasma of all subjects were maximal at the earliest time points examined, 15-30 min after smoking the cigarette containing [D 10]phenanthrene, and decreased thereafter. These results demonstrate that the formation of a PAH diol epoxide occurs rapidly in smokers. Because PAH diol epoxides are mutagenic and carcinogenic, the results clearly demonstrate immediate negative health consequences of smoking, which should serve as a major warning to anyone contemplating initiating tobacco use.
AB - Polycyclic aromatic hydrocarbons (PAH) are among the likely major causative agents for lung cancer in smokers. PAH require metabolic activation to exert their carcinogenic effects, and one important pathway proceeds through a three-step sequence resulting in the formation of diol epoxides, which react with DNA to produce adducts that can cause mutations and initiate the carcinogenic process. However, no previous published studies have examined this critical pathway in humans specifically exposed to PAH by inhalation of cigarette smoke. This study used a unique approach employing a stable isotope derivative of phenanthrene, the simplest PAH with a bay region, a feature closely associated with PAH carcinogenicity. Twelve subjects each smoked a cigarette to which [D10]phenanthrene had been added. Plasma was analyzed for [D10]r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4- tetrahydrophenanthrene ([D10]PheT), the major end product of the diol epoxide metabolism pathway of phenanthrene. The analysis was performed by gas chromatography-negative ion chemical ionization-tandem mass spectrometry, using [13C6]PheT as internal standard. The results demonstrated that the three-step pathway resulting in the formation of diol epoxides, as monitored by [D10]PheT, occurred with remarkable rapidity. Levels of [D10]PheT in plasma of all subjects were maximal at the earliest time points examined, 15-30 min after smoking the cigarette containing [D 10]phenanthrene, and decreased thereafter. These results demonstrate that the formation of a PAH diol epoxide occurs rapidly in smokers. Because PAH diol epoxides are mutagenic and carcinogenic, the results clearly demonstrate immediate negative health consequences of smoking, which should serve as a major warning to anyone contemplating initiating tobacco use.
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U2 - 10.1021/tx100345x
DO - 10.1021/tx100345x
M3 - Article
C2 - 21184614
AN - SCOPUS:79951837895
VL - 24
SP - 246
EP - 252
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
SN - 0893-228X
IS - 2
ER -