Tissue distribution of covalent DNA damage in mice treated dermally with cigarette 'tar': preference for lung and heart DNA.
The high incidence of lung cancer in smokers is thought to be related to the direct exposure of bronchial and pulmonary cells to carcinogens in inhaled cigarette smoke. Using a 32P-postlabeling assay for chemically induced covalent DNA alterations, we found that unfractionated, relatively non-polar cigarette smoke components bound preferentially to lung and heart DNA in female ICR mice. After 6 days of topical treatment with cigarette smoke condensate (CSC) equivalent to a total of 4.5 cigarettes, covalent DNA damages was estimated to be 6.2, 5.7, 3.9 and 1.9 times higher, respectively, in lung, heart, skin and kidney than in liver, ranging from approximately 1 adduct in 5.4 +/- 0.7 X 10(6) DNA nucleotides in lung to 1 adduct in 3.3 +/- 0.6 X 10(7) DNA nucleotides in liver. Spleen DNA was virtually adduct-free. Adducts occupied two extensive zones, designated diagonal radioactive zone (DRZ) 1 and DRZ 2, on TLC fingerprints. Preference for lung and heart DNA was also observed in mice treated for 1 or 3 days. An inverse association appeared to exist between the tissue distribution of CSC-induced covalent DNA damage and the reported activity of enzymes catalyzing the metabolism of xenobiotics (cytochrome P-450 monooxygenases, phase II enzymes) and toxic oxygen species (superoxide dismutase, catalase). The results suggest that the well-known pulmonary and cardiovascular organotropism of cigarette-smoking-associated adverse health effects may, in part, have its origin in the inherent capacity of cigarette smoke components to induce lesions in lung and heart DNA in a tissue-specific manner. Possible mechanisms and health implications of the preferential binding of presumably aromatic CSC constituents to lung and heart DNA are discussed.
Randerath
E
E
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Mittal
D
D
Randerath
K
K
D000287:Administration, Topical; D000818:Animals; D002855:Chromatography, Thin Layer; D004247:DNA / Q000032:analysis; D004249:DNA Damage; D005260:Female; D006321:Heart / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects; D008168:Lung / Q000032:analysis / Q000187:drug effects*; D051379:Mice; D009206:Myocardium / Q000032:analysis; D009708:Nucleotidases; D010947:Plants, Toxic; D015719:Single-Strand Specific DNA and RNA Endonucleases; D012867:Skin / Q000187:drug effects; D013638:Tars / Q000008:administration & dosage / Q000633:toxicity*; D014026:Nicotiana
D013638:Tars; C024746:tobacco tar; D004247:DNA; D009708:Nucleotidases; D015719:Single-Strand Specific DNA and RNA Endonucleases