Abstract
Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are among the most likely causes of lung cancer. PAHs require metabolic activation to initiate the carcinogenic process. Phenanthrene (Phe), a noncarcinogenic PAH, was used as a surrogate of benzo[α]pyrene and related PAHs to study the metabolic activation of PAHs in smokers. A dose of 10 μg of deuterated Phe ([D10]Phe) was administered to 25 healthy smokers in a crossover design, either as an oral solution or by smoking cigarettes containing [D10]Phe. Phe was deuterated to avoid interference from environmental Phe. Intensive blood and urine sampling was performed to quantitate the formation of deuterated r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene ([D10]PheT), a biomarker of the diol epoxide metabolic activation pathway. In both the oral and smoking arms approximately 6% of the dose was metabolically converted to diol epoxides, with a large intersubject variability in the formation of [D10]PheT observed. Two diagnostic plots were developed to identify subjects with large systemic exposure and significant lung contribution to metabolic activation. The combination of the two plots led to the identification of subjects with substantial local exposure. These subjects produced, in one single pass of [D10]Phe through the lung, a [D10]PheT exposure equivalent to the systemic exposure of a typical subject and may be an indicator of lung cancer susceptibility. Polymorphisms in PAH-metabolizing genes of the 25 subjects were also investigated. The integration of phenotyping and genotyping results indicated that GSTM1-null subjects produced approximately 2-fold more [D10]PheT than did GSTM1-positive subjects.
Footnotes
This study was supported by the National Institutes of Health National Cancer Institute [Grant CA-92025].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- PAH
- polycyclic aromatic hydrocarbon
- BaP
- benzo[α]pyrene
- Phe
- phenanthrene
- PheT
- r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene
- [D10]Phe
- deuterated Phe
- [D10]PheT
- deuterated PheT
- [D10]PheDE
- deuterated anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrophenanthrene
- BPDE
- benzo[α]pyrene-7,8-diol-9,10-epoxide
- GST
- glutathione transferase
- GSTM1
- GST mu 1
- PK
- pharmacokinetic
- AUC
- area under the curve
- CL
- clearance
- SBE
- single-base extension
- EPHX1
- epoxide hydrolase 1
- Aact
- total amount of [D10]PheDE formed during metabolic activation
- A(Phe,abs)
- amount of [D10]PheDE at the site of absorption
- A(Phe,abs),t = 0
- amount of [D10]PheDE at the site of absorption at time 0
- A(Phe,abs),t = T
- amount of [D10]Phe at the site of absorption at time T
- A(PheDE)
- amount of [D10]Phe in the body
- A(PhDE),t = 0
- amount of [D10]PheDE in the body at time 0
- A(PhDE),t = T
- amount of [D10]PheDE in the body at time T
- A(PhDE),t = ∞
- amount of [D10]PheDE in the body at time infinity
- A(PheT)
- amount of [D10]PheT in the body
- A(PheT),t= 0
- amount of [D10]PheT in the body at time 0
- A(PheT),t= T
- amount of [D10]PheT in the body at time T
- A(PheT),t= ∞
- amount of [D10]PheT in the body at time infinity
- AUC(Phe,abs)
- area under the C(Phe,abs)-time curve from time 0 to infinity
- AUC0T(Phe,abs)
- area under the C(Phe,abs)-time curve from time 0 to T
- AUC(Phe)
- area under the C(Phe)-time curve from time 0 to infinity
- AUC0T(Phe)
- area under the C(Phe)-time curve from time 0 to T
- AUC(PheDE)
- area under the C-(PheDE)-time curve from time 0 to infinity
- AUC0T(PheDE)
- area under the C(PheDE)-time curve from time 0 to T
- AUC(PheT)
- area under the C(PheT)-time curve from time 0 to infinity
- AUC0T(PheT)
- area under the C(PheT)-time curve from time 0 to T
- C(Phe,abs)
- concentration of [D10]Phe at the site of absorption
- C(Phe)
- plasma concentration of [D10]Phe
- C(PheDE)
- plasma concentration of [D10]PheDE
- C(PheT)
- plasma concentration of [D10]PheT
- fa
- the fraction of dose absorbed
- fact
- the fraction of dose converted to [D10]PheDE during first-pass activation
- fm
- the fraction of [D10]Phe converted to [D10]PheDE in the systemic circulation
- Xu(PheT)
- cumulative amount of [D10]PheT collected in the urine
- Xu(PheT),t = T
- amount of [D10]PheT collected in the urine at time T
- Xu(PheT),t = 48
- amount of [D10]PheT collected in the urine at 48 h
- Xu(PheT),t = ∞
- amount of [D10]PheT collected in the urine at time infinity.
- Received March 28, 2012.
- Accepted June 6, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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