Covalent binding of dibenzpyrenes and benzo[a]pyrene to DNA: evidence for synergistic and inhibitory interactions when applied in combination to mouse skin.
Several well-documented examples of human exposure to carcinogens involve complex mixtures of polycyclic aromatic hydrocarbons (PAHs). Although the biological properties of many pure PAHs have been investigated, less is known about their effects when present as components of mixtures. As the ability to form DNA adducts in vivo is generally indicative of carcinogenic activity of PAHs, we have compared the DNA binding potencies of dibenzo[a,e]pyrene (DB[a,e]P), dibenzo[a,e]pyrene (DB[a,h]P), dibenzo[a,i]pyrene (DB[a,i]P), dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P), when applied topically, either singly or in combination, to the skin of male Parkes mice. DNA isolated from the skin and lungs was analysed by 32P-postlabelling. The adducts formed by each PAH exhibited markedly different chromatographic mobilities on polyethyleneimine-cellulose TLC plates. The relative binding potencies of the compounds in both skin and lungs were: DB[a,l]P much greater than B[a]P greater than DB[a,h]P greater than DB[a,i]P greater than DB[a,e]P, in good agreement with their reported carcinogenicities in mouse skin. The majority of adducts were removed from DNA within 21 days of treatment, but low levels of adducts were found to persist for at least 3 months in both tissues. When DB[a,l]P, DB[a,e]P and B[a]P were applied together to mouse skin, a total binding 31% lower than expected was detected, while with a mixture of DB[a,e]P and B[a]P the binding to DNA in skin was 65% higher than expected from the binding levels of the carcinogens when applied singly. Other binary combinations of these three PAHs gave adduct levels similar to the sum of the binding levels of the individual components when applied singly. The results demonstrate the usefulness of 32P-post-labelling for the assessment of the DNA binding potencies of PAHs in mouse tissues, and for the detection of interactions between components of mixtures of carcinogens.
Hughes
N C
NC
Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
Phillips
D H
DH
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000633:toxicity; D001580:Benzopyrenes / Q000378:metabolism* / Q000633:toxicity; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000302:isolation & purification / Q000378:metabolism*; D004357:Drug Synergism; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D012867:Skin / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013329:Structure-Activity Relationship
D001580:Benzopyrenes; D002273:Carcinogens; D001564:Benzo(a)pyrene; D004247:DNA