Phenanthrene metabolism in smokers: use of a two-step diagnostic plot approach to identify subjects with extensive metabolic activation.
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.
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota, USA.
Jing
J
Wang
Yan
Y
Zhong
Steven G
SG
Carmella
J Bradley
JB
Hochalter
Diane
D
Rauch
Andrew
A
Oliver
Joni
J
Jensen
Dorothy K
DK
Hatsukami
Pramod
P
Upadhyaya
Stephen S
SS
Hecht
Cheryl L
CL
Zimmerman
D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010616:Phenanthrenes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D055815:Young Adult
D015415:Biomarkers; D002273:Carcinogens; D005982:Glutathione Transferase; D010616:Phenanthrenes; D011084:Polycyclic Aromatic Hydrocarbons; D014028:Tobacco Smoke Pollution; C502234:r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene; C031181:phenanthrene