Abstract
The role of organ-specific, enzymic release of alkylating intermediates in determining which tissue develops a tumour in response to a given N-nitrosamine has been evaluated on the basis of published data on the carcinogenicity of 62 N-nitrosamines that induce tumours in specific tissues in rats. A good correlation was noted between the metabolic capacity for N-nitrosamine activation and the organ in which tumours are induced. A relationship was also noted between the localization of carcinogen activating enzymes in rat tissues and the site at which the tumour developed following administration of N-(acetoxy) methyl-N-methylnitrosamine. This compound was shown to be cleaved by soluble enzymes equally efficiently in various rat tissues, such as liver, kidney, spleen and small intestinal mucosa, to yield the alkylating and mutagenic intermediates which are presumably those also formed from the parent N,N-dimethylnitrosamine by microsomal enzymes. N-(acetoxy)methyl-N-methylnitrosamine causes tumours of the gastrointestinal tract, although the parent N,N-dimethylnitrosamine rarely affects this site in rats.
The neurotropic carcinogen 3,3-dimethyl-1-phenyltriazene is known to undergo predominantly in the rodent liver oxidative N-mono-demethylation by microsomal enzymes to yield a carcinogenic, mutagenic, and alkylating intermediate, 3-methyl-1-phenyltriazene; however the parent compound produces extrahepatic tumours exclusively. To explain this alternative model of organ specificity, the half-life of 3-methyl-1-phenyltriazene was measured and found to be long enough to permit its distribution throughout the body. Furthermore, subcutaneous injection of 3-[C14-methyl]-1-phenyltriazene into rats yielded alkylated bases in nucleic acids of hepatic and extrahepatic tissues including brain, the major target organ of the parent compound 3,3-dimethyl-1-phenyltriazene. Eight hours after injection of 3-methyl-1-phenyltriazene the O 6 ∶ N 7-methylguanine ratio was found to be lowest in the liver and highest in the brain, indicating a low rate of O 6-methylguanine excision. Thus, for this carcinogen, the persistence of alkylated DNA bases may be a final determinant in tissue specific induction of tumours.
The implications of these data for the use of in vitro metabolic activation systems in short-term tests for detecting potential carcinogens are discussed.
Zusammenfassung
Die Rolle einer organspezifischen Freisetzung von alkylierenden Zwischenstufen aus N-Nitrosaminen in bezug auf ihre organotrope, karzinogene Wirkung, wurde anhand von Literaturdaten an 62 N-Nitrosaminen untersucht. Die Fähigkeit verschiedener Gewebe der Ratte, N-Nitrosamine metabolisch zu aktivieren, ließ sich gut mit Organen korrelieren, in denen nach Vergabe der N-Nitrosamine Tumoren erzeugt werden.
Ein ähnlicher Zusammenhang wurde beim Karzinogen N-(Acetoxymethyl)-N-methylnitrosamin beobachtet. Diese Nitrosoverbindung wurde durch lösliche Enzyme, die in gleich hoher Aktivität in der Leber, Niere, Milz und im mukösen Gewebe des Dünndarmes vorkommen, in alkylierende und mutagene Zwischenstufen gespalten, wobei wahrscheinlich die gleichen reaktiven Metaboliten freigesetzt werden, wie sie aus dem hepatokarzinogenen N,N-Dimethylnitrosamin durch mikrosomale Enzyme gebildet werden. Im Gegensatz zur letzteren Substanz, induziert jedoch N-(Acetoxy)methyl-N-methylnitrosamin bevorzugt Tumoren im Verdauungstrakt der Ratte.
3,3-Dimethyl-1-phenyltriazen, ein Karzinogen mit neurotroper Wirkung, wird hauptsächlich in der Leber von Nagetieren über eine oxidative N-Monodemethylierung in das karzinogene, direkt mutagene und alkylierende 3-Methyl-1-phenyltriazen überführt, während die Muttersubstanz überwiegend Tumoren außerhalb der Leber induziert. Die Halbwertzeit von 3-Methyl-1-phenyltriazen wurde in vitro bestimmt und für lang genug befunden, um eine Verteilung dieses Metaboliten im Organismus zu erlauben. Nach subkutaner Vergabe von 3-[14C-methyl]-1-phenyltriazen an Ratten wurden alkylierte Nukleinsäurebasen in der Leber und in anderen Geweben, einschließlich im Hirn, einem Zielorgan des karzinogenen 3,3-Dimethyl-1-phenyltriazens, gefunden wurden. Acht Stunden nach Injektion von 3-Methyl-1-phenyltriazen in Ratten, wurde das O 6 ∶ N 7-Methylguanin-Verhältnis am niedrigsten in Nukleinsäuren der Leber, aber am größten in denen des Hirngewebes gefunden. Diese Daten unterstreichen eine möglicherweise determinierende Rolle der Halbwertszeit bestimmter alkylierter DNS-Basen in vivo bei der selektiven Erzeugung von Hirntumoren durch 3,3-Dimethyl-1-phenyltriazen.
Die Bedeutung dieser Befunde, im Hinblick auf die Benutzung von Organhomogenaten als Aktivierungsystem in Kurzzeit-Testen zur Erfassung potentieller chemischer Karzinogene, wird diskutiert.
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Bartsch, H., Margison, G.P., Malaveille, C. et al. Some aspects of metabolic activation of chemical carcinogens in relation to their organ specificity. Arch. Toxicol. 39, 51–63 (1977). https://doi.org/10.1007/BF00343275
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DOI: https://doi.org/10.1007/BF00343275