Cigarette smoking enhances the metabolic activation of the polycyclic aromatic hydrocarbon phenanthrene in humans

Kai Luo, Xianghua Luo, Wenhao Cao, J Bradley Hochalter, Viviana Paiano, Christopher J Sipe, Steven G Carmella, Sharon E Murphy, Joni Jensen, Stephen Lam, Andrew P Golin, Lori Bergstrom, David Midthun, Naomi Fujioka, Dorothy Hatsukami, Stephen S Hecht

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)570-577
Number of pages8
Issue number4
Early online dateDec 2020
StatePublished - Dec 15 2020

Bibliographical note

Publisher Copyright:
© 2020 The Author(s). Published by Oxford University Press. All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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