Abstract 4530: Tissue distribution, excretion and pharmacokinetics of the environmental pollutant and the tobacco smoke constituent dibenzo[a,l]pyrene in mice

Polycyclic aromatic hydrocarbon (PAH) has been shown to induce cancers after metabolic activation. DB[a,l]P is the most potent carcinogenic PAH found in tobacco smoke to date in rodent model systems. DB[a,l]P has been identified in mainstream cigarette smoke, soil and diesel exhaust particulate. Studies reported in the literature including our own demonstrated that administration of DB[a,l]P by i.p. or oral application in mice is known to induce tumors in organ sites including oral cavity, ovary, lung, mammary and liver. We further demonstrated that DB[a,l]P exerts its oral tumorigenicity mainly through the formation of its diol epoxides. However, detailed studies aimed at elucidating the tissues distribution and biological fate of DB[a,l]P remain to be determined. Therefore, a radiotracer experiment was conducted. Six weeks old female B6C3F1 mice received a single dose of [3H]-DB[a,l]P (1.512 Ci mmol-1 in dimethyl sulfoxide, 1.07 mg Kg-1 body weight) via gavage and were individually housed in metabolism cages (the same strain of mice used in carcinogenicity studies). Mice were randomly assigned into 7 groups (3/group) and sacrificed at0, 40 min, 2 h, 6 h, 24 h, 72 h and 1 week after carcinogen administration. Feces, urine, blood and tissues including ovary, mammary, uterus, liver, stomach, intestine, pancreas, spleen, kidney, bladder, and lung were collected. Approximately 8.5 ± 0.93% and 73.21± 9.58% of the radioactivity was eliminated in feces after 6 and 24 h, respectively. After 72 h and 1 week, 89.94 ± 7.00% and 91.40 ± 7.23% of the radioactivity was recovered in feces, respectively. The total urine excretion of the radioactivity was less than 2% after 1 week. We constructed the log (plasma level)-time curve for [3H]-DB[a,l]P given in a single oral dose to describe the absorption and elimination rate process, and a linear plot was observed on the elimination phase from 6 hr to 1 week (γ2 = 0.999). Therefore, the pharmacokinetic analysis of DB[a,l]P was conducted using a one compartment open model using Phoenix® WinNonlin 6.3 (Pharsignt Corp, Mt. View, CA). In Plasma, DB[a,l]P reached its Tmax at about 10 hr and the elimination half-life (t1/2) was about 49 h. We found that tissues in digestive tract including stomach and intestine reached their highest radioactivity after 40 min, followed by lung after 2 hr, for remaining tissues, mammary, liver, pancreas, kidney and blood (6 hr), and ovary, uterine, spleen and bladder (24 hr). After 1 week, the concentration of radioactivity in stomach and intestine dropped to less than 2% of the radioactivity measured at 24 h; however, more than 20% of the radioactivity in ovary, mammary, lung and liver (target tissues) were retained. The varied elimination rates of radioactivity among blood, target tissues and non-target tissues may provide insights that can, in part, account for the carcinogenicity of DB[a,l]P. Support: CA173465 and ES020411. Citation Format: Kun-Ming Chen, Yuan-Wan Sun, Cesar Aliaga, Alaa Awad, Krishne Gowda, Shantu Amin, Karam El-Bayoumy. Tissue distribution, excretion and pharmacokinetics of the environmental pollutant and the tobacco smoke constituent dibenzo[a,l]pyrene in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4530. doi:10.1158/1538-7445.AM2015-4530