Summary
Metabolic activation steps involved in carcinogenesis by several aromatic amines, their N-acetylated derivatives, and dialkylnitrosamines are reviewed. N-Hydroxylation is the first activation step in the carcinogenesis by 2-acetylaminofluorene (AAF), other aromatic amides and amines. The cytochrome P-450 enzyme system is involved in AAF N-hydroxylation. Reconstitution studies indicate that the specificity of AAF N-hydroxylation is determined by the source of cytochrome P-450. Further metabolic activations of aromatic N-hydroxy amines and amides via sulfate, acetyl, and glucuronyl transfer reactions in the hepatic and extrahepatic tissue carcinogenesis by AAF, 4-aminobiphenyl, 2-naphthylamine, and aminoazo dyes are discussed. Dialkylnitrosamines are shown to be activated by oxidative dealkylation via cytochrome P-450 enzyme systems. Other microsomal enzymes are also believed to be involved in oxidation of these compounds. Tissue and species show specificity in oxidative metabolism of these carcinogens. During oxidation of these compounds, reactive alkylating species are generated which interact covalently with cellular macromolecules. DNA methylation does occur during NADPH dependent oxidation of dimethylnitrosamine by liver microsomes. High pressure liquid chromatography separation of acid hydrolyzed DNA indicates the presence of methylated bases including N-7 methylguanine und O6-methylguanine. It is believed that the presence of O6-alkylguanine in DNA may be responsible for the initiation of carcinogenesis by dialkylnitrosamines.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bartsch H, Dworkin M, Miller JA, Miller EC (1972) Electrophilic N-acetoxyaminoarenes derived from carcinogenic N-hydroxy-N-acetylamino arenes by enzymatic deacetylation and transacetylation in rat liver. Biochim Biophys Acta 286:272–298
Coon MJ, Vermilion JL, Vatsis KP, French JS, Dean WL, Huagen DA (1977) Biochemical studies on drug metabolism. Isolation of multiple forms of liver microsomal cytochrome P-450. In: Jerina (ed) Drug metabolism concepts. ASC symposium series No. 44. Am Chem Soc, Washington, DC, pp 46–71
Cramer JW, Miller JA, Miller EC (1960) N-Hydroxylation: A new metabolic reaction observed in the rat with the carcinogen 2-acetylaminofluorene. J Biol Chem 235:885–888
Czygan P, Greim H, Garro AJ, Hutterer F, Schaffner F, Popper H, Rosenthal O, Cooper DY (1973) Microsomal metabolism of dimethylnitrosamine and cytochrome P-450 dependency of its activation to a mutagen. Cancer Res 33:2983–2986
DeBaun JR, Miller EC, Miller JA (1970) N-Hydroxy-2-acetylaminofluorene sulfotransferase: Its probable role in carcinogenesis and in protein (methion-S-yl)-binding in rat liver. Cancer Res 30:577–595
Druckrey H, Preussmann R, Ivankovic S, Schmahl D (1967) Organotrope carcinogene Wirkungen bei 65 verschiedenen N-nitrosoverbindungen an BD-Ratten. Z Krebsforsch 69:103–201
Guengerich FP (1977) Separation and purification of multiple forms of cytochrome P-450. Activities of different forms of cytochrome P-450 towards several compounds of environmental interest. J Biol Chem 252:3970–3979
Gutmann HR, Bell P (1977) N-Hydroxylation of arylamindes in the rat and guinea pig. Evidence for substrate specificity and participation of cytochrome P-450. Biochim Biophys Acta 498:229–243
Heath DF (1962) The decomposition and toxicity of dialkylnitrosamines in rats. Biochem J 85:72–91
Hong YS, Lotlikar PD (1978) Lipid requirement for 2-acetylaminofluorene (AAF) N-and ring-hydroxylation by reconstituted hamster liver microsomal enzyme system. Proc Am Assoc Cancer Res 19:128
Irving CC (1962) N-Hydroxylation of the carcinogen 2-acetylaminofluorene by rabbit liver microsomes. Biochim Biophys Acta 65:564–566
Irving CC (1964) Enzymatic N-hydroxylation of the carcinogen 2-acetylaminofluorene and the metabolism of N-hydroxy-2-acetylaminofluorene-9-14C in vitro. J Biol Chem 239:1589–1596
Irving CC (1970) Conjugates of N-hydroxy compounds. Fishman WH ed. In: Metabolic conjugation and metabolic hydrolysis Vol 1. Academic Press New York 53–119
Irving CC (1979) Species and tissue variations in the metabolic activation of aromatic amines. In: Griffin AC, Shaw CR (eds) Carcinogens: Identification and mechanism of action. Raven Press, New York, pp 211–227
Jensen DE, Lotlikar PD, Magee PN (1979) Identification of methylated bases in DNA modified by microsomally activated dimethylnitrasamine. Proc Am Assoc Cancer Res 20:121
Kadlubar FF, Miller JA, Miller EC (1976a) Microsomal N-oxidation of the hepatocarcinogen N-methyl-4-aminoazobenzene and the reactivity of N-hydroxy-N-methyl-4-aminoazobenzene. Cancer Res 36:1196–1206
Kadlubar FF, Miller JA, Miller EC (1976b) Hepatic metabolism of N-hydroxy-N-methyl-4-aminoazobenzene and other N-hydroxyarylamines to reactive sulfuric acid esters. Cancer Res 36: 2350–2359
Kadlubar FF, Miller JA, Miller EC (1977) Hepatic microsomal N-glucuronidation and nucleic acid binding of N-hydroxy arylamines in relation to urinary bladder carcinogenesis. Cancer Res 37:805–814
King CM (1974) Mechanism of reaction, tissue distribution, and inhibition of arylhydroxyamic acid acyltransferase. Cancer Res 34:1503–1515
King CM (In Press) (1980) The formation, metabolic activation by N,O-acyltransfer and hydrolysis of N-acyl-N-arylamine derivatives. Thorgeirsson SS, Weisburger EK, King CM, Schribner JD eds. In: Carcinogenic and mutagenic N-substituted aryl compounds. J Natl Cancer Inst Monograph
King CM, Phillips B (1969) N-hydroxy-2-fluorenylacetamide. Reaction of the carcinogen with guanosine, ribonucleic acid, deoxyribonucleic acid and protein following enzymatic deacetylation esterification. J Biol Chem 244:6209–6216
Lake BG, Phillips JC, Cottrell RC, Gangolli SD (1978) The possible involvement of a microsomal amine oxidase enzyme in hepatic dimethylnitrosamine degradation in vitro. In: Gorrod JN (ed) Biological oxidation of nitrogen. Elsevier, Amsterdam, pp 131–135
Lotlikar PD, Baldy WJ, Jr., Dwyer EN (1975) Dimethylnitrosamine demethylation by reconstituted liver microsomal cytochrome P-450 enzyme system. Biochem J 152:705–708
Lotlikar PD, Baldy WJ, Jr., Nyce JW, Dwyer EN (1976) Dealkylation of dimethyl and diethylnitrosamine by tissue microsomal enzyme system. Proc Am Assoc Cancer Res 17:204
Lotlikar PD, Enomoto M, Miller JA, Miller EC (1967) Species variations in the N-and ring-hydroxylation of 2-acetylaminofluorene and effects of 3-methylcholanthrene pretreatment. Proc Soc Exp Biol Med 125:341–346
Lotlikar PD, Hong YS (1980) Microsomal N and C oxidations of carcinogenic aromatic amines and amides. In: Thorgeirsson SS, Weisburger EK, King CM, Scribner JD (eds) Carcinogenic and mutagenic N-substututed aryl compounds. J Natl Cancer Inst Monograph (in press)
Lotlikar PD, Hong YS, Baldy WJ, Jr. (1978) Cytochrome P-450-dependent N-hydroxylation of 2-acetylaminofluorene. In: Gorrod JW (ed) Biological oxidation of nitrogen. Elsevier, Amsterdam, pp 185–193
Lotlikar PD, Luha L, Zaleski K (1974) Reconstituted hamster liver microsomal enzyme system for N-hydroxylation of the carcinogen 2-acetylaminofluorene. Biochem Biophys Res Commun 59:1349–1355
Lotlikar PD, Zaleski K (1974) Inhibitory effect of carbon monoxide on the N- and ring-hydroxylation of 2-acetylamidofluorene by hamster hepatic microsomal preparations. Biochem J 144:427–430
Loveless A (1969) A possible relevance of O-6 alkylation of deoxyguanosine to the mutagenicity and carcinogenicity of nitrosamines and nitrosamides. Nature 223:206–207
Magee PN, Pegg AE, Swann PF (1975) Molecular mechanisms of chemical carinogenesis. In: Grundmann E (ed) Handbuch der Allgemeinen Pathologie. Springer Berlin Heidelberg New York, pp 329–420
Miller JA, Miller EC (1969) The metabolic activation of carcinogenic aromatic amines and amides. Prog Exp Tumor Res 11:273–301
Miller JA, Miller EC (1977) Ultimate chemical carcinogens as reactive mutagenic electrophiles. In: Hiatt HH, Watson JD, Winsten JA (eds) Origins of human cancer vol B. Cold Spring Harbor Lab, Cold Spring Harbor, New York, pp. 505–527
Montesano R, Magee PN (1974) Comparative metabolism in vitro of nitrosamines in various animal species including man. In: Montesano R, Tomatis L (eds) Chemical carcinogenesis essays. IARC Scientific Publications, No 10, Lyon France, pp 39–56
Pegg AF (1977) Formation and metabolism of alkylated purines: Possible role in carcinogenesis by N-nitroso compounds and alkylating agents. Adv Cancer Res 25:195–269
Scott TS (1962) Carcinogenic and chronic toxic hazards of aromatic amines. Elsevier, Amsterdam
Thorgeirsson SS, Jallow DJ, Sasame HA, Green I, Mitchell JR (1973) The role of cytochrome P-450 in N-hydroxylation of 2-acetylaminofluorene. Mol Pharmacol 9:398–404
Weisburger JH, Weisburger Ek (1973) Biochemical formation and pharmacological, toxicological, and pathological properties of hydroxylamines and hydroxyamic acids. Pharmacol Rev 25:1–66
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lotlikar, P.D. Metabolic activation of aromatic amines and dialkylnitrosamines. J Cancer Res Clin Oncol 99, 125–136 (1981). https://doi.org/10.1007/BF00412448
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00412448