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 non-carcinogenic PAH, was used as a surrogate of benzo[α]pyrene (BaP) and related PAHs to study the metabolic activation of PAHs in smokers. A dose of 10 μg 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. 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 an average of approximately 6% of the dose was metabolically converted to diol epoxides, with a large inter-subject 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, respectively. 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, which 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.
A population pharmacokinetic analysis was also tried as an alternative approach to identify subjects with extensive activation, but the analysis was not completely successful. The preliminary statistical analysis indicated a correlation between renal function and an individual’s capacity to activate PAHs, which may deserve further investigation. A simulation project based on the pharmacokinetic data of 25 subjects was carried out to simulate the metabolic activation of [D10]Phe in 350 subjects after oral dosing and smoking. The simulation suggested that the collection of a 6-hr urine sample in both treatment arms should be conducted in the future large-scale trials in order to efficiently assess the hypothesized correlation between extensive activation and high lung cancer risk.
University of Minnesota Ph.D. dissertation. June 2012. Major: Pharmaceutics. Advisor: Dr. Cheryl Zimmerman. 1 computer file (PDF); vii, 112 pages, appendices I-IV.
Quantitation of the metabolic activation of phenanthrene in smokers:potential use in the assessment of lung cancer susceptibility.
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