TY - JOUR
T1 - Cigarette smoking enhances the metabolic activation of the polycyclic aromatic hydrocarbon phenanthrene in humans
AU - Luo, Kai
AU - Luo, Xianghua
AU - Cao, Wenhao
AU - Bradley Hochalter, J.
AU - Paiano, Viviana
AU - Sipe, Christopher J.
AU - Carmella, Steven G.
AU - Murphy, Sharon E.
AU - Jensen, Joni
AU - Lam, Stephen
AU - Golin, Andrew P.
AU - Bergstrom, Lori
AU - Midthun, David
AU - Fujioka, Naomi
AU - Hatsukami, Dorothy
AU - Hecht, Stephen S.
N1 - Publisher Copyright:
© 2020 The Author(s). Published by Oxford University Press. All rights reserved.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - Although it is well established that human cytochrome P450 1 family enzymes are induced by cigarette smoking through activation of the Ah receptor, it is not known whether this leads to increased metabolic activation or detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAH), which are present in cigarette smoke and the general environment. We gave oral doses of deuterated phenanthrene ([D10]Phe), a non-carcinogenic surrogate of carcinogenic PAH such as benzo[a]pyrene, to smokers (N = 170, 1 or 10 μg doses) and non-smokers (N = 57, 1 μg dose). Bioactivation products (dihydrodiol and tetraol) and detoxification products (phenols) of [D10]Phe were determined in 6-h urine to obtain a comprehensive metabolic profile. Cigarette smoking increased the bioactivation of [D10]Phe and decreased its detoxification resulting in significantly different metabolic patterns between smokers and non-smokers (P < 0.01), consistent with increased cancer risk in smokers. The Phe bioactivation ratios ([D10]PheT/total [D9]OHPhe) were significantly higher (2.3 (P < 0.01) to 4.8 (P < 0.001) fold) in smokers than non-smokers. With solid human in vivo evidence, our results for the first time demonstrate that cigarette smoking enhances the metabolic activation of Phe, structurally representative of carcinogenic PAH, in humans, strongly supporting their causal role in cancers caused by smoking. The results suggest potential new methods for identifying smokers who could be at particularly high risk for cancer.
AB - Although it is well established that human cytochrome P450 1 family enzymes are induced by cigarette smoking through activation of the Ah receptor, it is not known whether this leads to increased metabolic activation or detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAH), which are present in cigarette smoke and the general environment. We gave oral doses of deuterated phenanthrene ([D10]Phe), a non-carcinogenic surrogate of carcinogenic PAH such as benzo[a]pyrene, to smokers (N = 170, 1 or 10 μg doses) and non-smokers (N = 57, 1 μg dose). Bioactivation products (dihydrodiol and tetraol) and detoxification products (phenols) of [D10]Phe were determined in 6-h urine to obtain a comprehensive metabolic profile. Cigarette smoking increased the bioactivation of [D10]Phe and decreased its detoxification resulting in significantly different metabolic patterns between smokers and non-smokers (P < 0.01), consistent with increased cancer risk in smokers. The Phe bioactivation ratios ([D10]PheT/total [D9]OHPhe) were significantly higher (2.3 (P < 0.01) to 4.8 (P < 0.001) fold) in smokers than non-smokers. With solid human in vivo evidence, our results for the first time demonstrate that cigarette smoking enhances the metabolic activation of Phe, structurally representative of carcinogenic PAH, in humans, strongly supporting their causal role in cancers caused by smoking. The results suggest potential new methods for identifying smokers who could be at particularly high risk for cancer.
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U2 - 10.1093/carcin/bgaa137
DO - 10.1093/carcin/bgaa137
M3 - Article
C2 - 33319219
AN - SCOPUS:85106069531
SN - 0143-3334
VL - 42
SP - 570
EP - 577
JO - Carcinogenesis
JF - Carcinogenesis
IS - 4
ER -