BIOMARKERS AND OCCUPATIONAL HEALTH: PROGRESS AND PERSPECTIVES by Mortimer L.Mendelsohn John P.Peeters Mary Janet Normandy

Author:Mortimer L.Mendelsohn John P.Peeters Mary Janet Normandy
Language: eng
Format: epub
Tags: Explore Science
Publisher: NATIONAL ACADEMY PRESS
Published: 1995-01-16T00:00:00+00:00

RECENT TECHNICAL ADVANCES IN BIOMARKERS RESEARCH

Mutant p21 Protein as a Biomarker of Chemical Carcinogenesis in Humans

Paul W.Brandt-Rauf, Marie-Jeanne Marion, and Immaculata DeVivo

Vinyl chloride (VC) is a known animal and human carcinogen which has been linked to the development of an unusual sentinel neoplasm, angiosarcoma of the liver (ASL) (ATSDR, 1993). In recent years, considerable insight has been gained into the potential carcinogenic mechanism of VC (Figure 1). VC is primarily metabolized in the liver by the cytochrome P450 2E1 system, and the electrophilic metabolites, chloroethylene oxide (CEO) and chloroacetaldehyde (CAA), are believed to be the most important in terms of carcinogenesis (ATSDR, 1993). CEO and CAA react with DNA bases to form adducts that are mutagenic in bacterial systems and mammalian cells (McCann et al., 1975; Huberman et al., 1975; Singer et al., 1988). Four DNA adducts have been identified in reactions with nucleic acids in vitro and in animals exposed to VC: 7-(2?-oxoethyl) guanine; 1,N6-ethenoadenine; 3,N4ethenocytosine; and N2,3-ethenoguanine (ATSDR, 1993).

In animal experiments, the oxoethyl adduct is the major liver DNA adduct formed, representing 98% of all adducts, but it is the least persistent with a half-life of about 62 hours (Barbin et al., 1985). By contrast, the less common etheno adducts are highly persistent with a half-life of more than 30 days, suggesting that they are poorly recognized by the liver DNA repair system (Swenberg et al., 1992). Etheno adducts are known to be capable of causing miscoding (Barbin and Bartsch, 1986), and, in in vitro assays, the most frequent mutation induced by these adducts is a G.C?A.T transition which has been attributed specifically to the occurrence of the etheno guanine adduct (Cheng et al., 1991). One site where such G?A transitions are apparently produced is at the second base of codon 13 of ras oncogenes (Boivin et al., 1993; Marion et al., 1991, 1993). For example, in a study of ras gene mutations by allele specific oligonucleotide hybridization in tumors of VC-exposed rats, 1 of 5 (20%) ASLs was found to contain a G?A transition at the second base of codon 13 of the N-ras-A gene (Boivin et al., 1993).

FIGURE 1. Proposed carcinogenic mechanism of vinyl chloride in the production of angiosarcomas of the liver.

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