Metabolism cyclic nitrosamines

Cyclic nitrosamines are among the most potent and environmentally significant nitrosamine carcinogens. Like the acyclic nitrosamines, metabolism is necessary for their carcinogenicity. Elucidation of the specific metabolic pathways of cyclic nitrosamine activation and detoxification is a challenging problem, and considerable progress has been achieved in recent years. In this chapter, we will review metabolic studies on N-nitrosopyrrolidine (NPYR), N -nitrosonornicotine (NNN), N-nitrosopiperidine (NPIP), N-nitrosohexamethyleneimine (NHEX), N-nitrosomorpholine (NMOR),... 

These studies on NPYR are typical of the state of the art in cyclic nitrosamine metabolism ai d activation. The major metabolic pathways have been rather well characterized, but data on the relationship of these pathways to carcinogenesis are limited. This is especially true of the organospecific effects of NPYR and the other cyclic nitrosamines. For example, the main target organs for NPYR in the Syrian golden hamster are the trachea and nasal cavity rather than the liver. This is in spite... 

Our studies on cyclic nitrosamine metabolism are supported by NCI Grants CA-21393, CA23901, and CA12376. This is paper Number 34 in A Study of Chemical Carcinogenesis. ... 

Syndex, C.M./ Farelly, J.G. and Lijinsky, W., Metabolism of Three Cyclic Nitrosamines in Sprague Dawley Rats , Cancer Res, 1 77, 37, 3530--3532. 

Human Cultured bronchi Comparative metabolism of acyclic and cyclic nitrosamines 178... 

Subcellular in vitro studies on cyclic nitrosamines have focused on //-nitrosopyrrolidine (NPYR), A-nitrosopiperidine (NPIP), A-nitrosomorpholine (NMOR), and A -nitrosonornicotine (NNN). Since a-hydroxylation is a likely mechanism of activation for cyclic nitrosamines, metabolic studies have been concerned primarily with this process. 

Studies on the metabolism of cyclic nitrosamines in organ culture systems have been carried out on NPYR, NPIP, NNN, and A, 7V -dinitrosopiperazine (DNP). In cultured human bronchi, NPYR, NPIP, and, to a lesser extent, DNP, were metabolized to CO2 178). All three nitrosamines were bound to protein and DNA of the bronchial explants. In cultured human colon, NPYR and DNP were metabolized to CO2 and were bound to DNA and protein (75). Low levels of binding were observed for NNN and NPIP. 

N-Nitrosamines are formed during processing and smoking of tobacco products. Proteins, agricultural chemicals and alkaloids in tobacco products serve as major precursors for volatile, nonvolatile, and tobacco-specific nitrosamines (Figure 1). In this review we will summarize the progress achieved in respect to tobacco nitrosamines since the last ACS symposium in Boston in June of 1978 (J ). Additional papers will review the metabolism of cyclic N-nitrosamines, including that of N -nitrosonornicotine 1) and the correlation between tobacco and alcohol consumption and cancer of the upper alimentary tract (J ). 

The formation of NNN, NNK, and NNA from nicotine probably involved the intermediacy of cyclic iminium salts, as shown in Figure 5 (28). These salts can undergo hydrolysis to the free amines which are nitrosated, or at near neutral pH, can be directly nitrosated to give nitrosamines. The formation of nitrosamines from iminium salts under neutral conditions has been demonstrated in at least two studies and is of interest because iminium salts are known to be intermediates in the mammalian metabolism of nicotine (26,29,30,31). The possibility that tobacco bacteria could nitrosate nicotine via this pathway is currently under investigation. 

In retrospect, the development and standardization of S-9 has centered around a limited number of chemical types, i.e., iV-nitrosamines, aromatic amines, and polycyclics. Accordingly, the ability of microbial systems supplemented with S-9 to detect these chemicals has been rather consistent. However, the converse also appears true chemicals, other than those types with which the testing has been standardized, that are metabolized in vivo to their active forms are not as consistently detected in such in vitro testing. While further discussion of this point is reserved for later, suffice it here to note that, in general, poorly activated types include azonaphthol dyes carbamyl and thiocarbamyl compounds phenyls polyhalogenated aromatics, cyclics, and aliphatics benzodioxoles and symmetrical hydrazines. 

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