Chemical carcinogenesis metabolic activation

Anderson RS (1978b) Developing an invertebrate model for chemical carcinogenesis metabolic activation of carcinogens. Comp Pathobiol 4 11-24 Anderson RS (1985) Metabolism of a model environmental carcinogen by bivalve molluscs. Mar Env Res 17 137-140... 

Some chemicals require metabolic activation (addition of microsomal enzymes) prior to showing mutagenic activity thus, data are given as number of revertants without/with metabolic activation. The Ames test has thus far demonstrated a strong correlation between positive carcinogenesis in animal tests and mutagenicity in the Ames test (1, U). However, positive results from the Ames test do not conclusively show human risk. 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

Chemical carcinogenesis by polycyclic aromatic hydrocarbons (PAHs) is a multi-step process in which each of the steps must occur if a neoplasm is to develop. Thus, exposure to PAHs alone is not necessarily sufficient for the induction of a tumor. Many of these factors are summarized below and are discussed in various chapters of this volume. Considered here will be those factors influencing the reactions of the metabolically activated forms of the PAHs with DNA and the ways in which adducts may be detected and characterized. 

Historically the process of activation has almost exclusively been studied by metabolizing compounds with liver preparations, leading most investigators in chemical carcinogenesis to think that... 

Although aminoacyl-tRNA synthetases are necessary for protein synthesis in all tissues, their importance in chemical carcinogenesis is difficult to assess. Mutation induction by this pathway has been studied extensively (123), yet metabolic activation in a carcinogen-target tissue has not been demonstrated. The only exception is hepatic prolyl-tRNA synthetase activation of N-hydroxy-Trp-P-2 however, hepatic O-acetylation of this substrate also occurs to an appreciable extent (12). Further investigations involving the use of specific enzyme inhibitors would be helpful in addressing this problem. 

Beland, F.A. and Kadlubar, F.F. (1990). Metabolic activation and DNA adducts of aromatic amines and nitroaromatic hydrocarbons. In Chemical Carcinogenesis and Mutagenesis, Cooper, C.S. and Grover, P.L. (eds), p. 267. Springer Verlag, Secaucus... 

As discussed in detail in Section 5, with chemical carcinogens, the route of exposure can be an important determinant of the site of cancer induction, particularly with direct-acting carcinogens which may act at the initial point of contact. For the majority of carcinogens, however, which require metabolic activation, the location in the body of activating enzymes is thought to be the major determinant of the site of carcinogenesis. 

These results implicate BHT as having a role in the activation, initiation or early promotional phase of DMBA-induced chemical carcinogenesis. A definite possibility is that it may require this period of time to allow for the induction of specific metabolic enzymes involved in the handling of DMBA. This time may be required for the attainment of sufficient levels in the tissues to allow effectiveness as an inhibitor. Further studies are certainly needed to narrow the wide range of possibilities. 

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