Tobacco Documents Online

I I I I I I I I I I I I I I I EFFECT OF DIETARY RESTRICTION ON BENZO[A]PYRENE (B(A)P) METABOLIC ACTIVATION AND PULMONARY B(A)P-DNA ADDUCT FORMATION IN MICE Chen Wen* and Chou Ming W.** * Institute for Chemical Carcinogenesis, Guangzhou Medical College, Guangzhou, China ** National Center for Toxicological Research, Jefferson, Arkansas, USA Dietary restriction (DR) is a paradigm which significantly reduces chronic disease,such as spontaneous tumor incidence, and expands the maximum lifespan of laboratory animals. Numerous investigations have demonstrated that DR in laboratory animals also effectively reduces the incidence of chemically-induced tumors, including mouse skin tumorigenesis induced by benzo(a)pryrene (B(a)P), rat mammary gland tumors produced by 7,12-dimethylbenz[a]anthracene, and hepatocarcinoma produced by aflatoxin 131 (AFBI). Since hepatic microsomal xenobiotic metabolizing enzyme activities can be altered by reducing the calorie intake of laboratory animals, DR may be an important factor to modulate the initiation process of chemically-induced carcinogenesis. Previously, we have used AFB1 and B(a)P as model chemical carcinogens to study the effects of DR on hepatic activation and detoxification of these compounds in male Fischer 344 rats. In this study, the metabolic activation of B(a)P in mouse lungs, in terms of the B(a)P-DNA adduct formation and removal were examined. Acute DR (60% of the food consumption of ad libitum (AL)-fed mice for 7 weeks) reduced the body weight of male B6C3F1 mice. Unlike the total B(a)P-DNA binding activity which was significantly enhanced in DR-mouse livers, the total B(a)P-DNA adduct formation in mouse lungs measured at 48 hours after the mice were treated with [°H]B(a)P was only marginally increased. However, the in vivo formation of the specific 10-(N- deoxyguanosinyl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-B(a)P (B(a)P-N2-dG), formed from B(a)P-7-8- dihydrodiol-9,10-epoxide (BPDE) with DNA (detected by the'P-postlabeling technique), was found to be greater in DR mice than in AL-fed animals. The formation of B(a)P-N2-dG adducts in mouse lung from the mice treated with a single dose of ['H]B(a)P showed a peak at 48 hours after dosing. The average increase of the major form of B(a)P-DNA adducts was 22% and may be attributed to the increase of mouse lung microsomal cytochrome P4501Aldependent B(a)P metabolizing enzyme activity. Using an in vitro microsome-dependent system, the aryl hydrocarbon hydroxylase (AHH) activity and B(a)P- DNA adduct formation were measured. Both the in vitro AHH activity and calf-thymus DNA-B(a)P adduct formation were greater in DR mice than in AL animals. Our results indicate that the effect of DR on the metabolic activation of B(a)P in mouse lung is dependent upon the DR-induced cytochrome P4501A1-dependent B(a)P metabolizing enzyme activity. A comparison of metabolic activation of B(a)P in mouse lungs with that of mouse-livers will also be presented.  ' o w ~ -4 W ~ N W I