Induced mutation

A large number of polycyclic aromatic hydrocarbons are known Many have been synthesized m the laboratory and several of the others are products of com bustion Benzo[a]pyrene for example is present m tobacco smoke contaminates food cooked on barbecue grills and collects m the soot of chimneys Benzo[a]pyrene is a carcinogen (a cancer causing substance) It is converted m the liver to an epoxy diol that can induce mutations leading to the uncontrolled growth of certain cells... 

Benzene oxide and compounds derived from it are carcinogenic and can react with DNA to induce mutations This difference m the site of biological oxidation—ring versus side chain—seems to be responsible for the fact that benzene is carcinogenic but toluene is not... 

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

Penicillins. Since the discovery of penicillin in 1928 as an antibacterial elaborated by a mold, Penicillium notatum the global search for better antibiotic-producing organism species, radiation-induced mutation, and culture-media modifications have been used to maximize production of the compound. These efforts have resulted in the discovery of a variety of natural penicillins differing in side chains from the basic molecule, 6-aminopenici11anic acid [551-16-6], These chemical variations have produced an assortment of dmgs having diverse pharmacokinetic and antibacterial characteristics (see Antibiotics, P-lactams). 

Each of the following ethers has been shown to be or is suspected to be a mutagen, which means it can induce mutations in test cells. Write the structure of each of these ethers. 

Brcimer, L.H. (1988). Ionizing radiation-induced mutation. Br. J. Cancer 57, 6-18. 

Oiler, A.R. and Thilly, W.G. (1992). Mutational spectra in human jS-cells. Spontaneous, oxygen and hydrogen peroxide-induced mutations at the hprt gene. J. Mol. Biol. 228, 813-826. 

The results on the cellular protection against N()2 can be interpreted as the N()2 reacting with the three antioxidants to produce their radicals, with ascorbic acid reacting least efficiently, probably due to the lower reduction potential of its radical. Moreover, Arroyo et al. (1992) reported that NO - and N02 -induced mutations in Salmonella typhimurium TA1535 were inhibited efficiently by P-CAR and tocopherols, but not at all by ascorbic acid. 

Novicik, A. and Szilard, L. (1951). Genetic mechanisms in bacteria and bacterial viruses. I. Experiments on spontaneous and chemically induced mutations of bacteria growing in the chemostat. Cold Spring Harbor Symposia on Quantitative Biology 16 337-343. 

On the other hand, the observation that 95% of the UV induced base substitution mutations arose at the very sites (pyrimidine-pyrimidine sequences) where the major fraction of UV damage is deposited suggested that at least the UV induced mutations were targeted (24). 

Table III. BPDE-Induced Mutations at the Three TAC Tyrosine Codons...

BPDE-induced mutations in plasmid borne genes can be dependent on umuC (75) ... 

Salmonella typhimurium. Although most nitro PAHs are direct-acting mutagens in Salmonella typhimurium, these compounds must be metabolized to bind covalently to DNA (71,92,112). S. typhimurium contains a family of nitroreductases which are capable of reducing nitro PAHs, and strains which are deficient in these enzymes generally show decreased sensitivity toward nitro PAH-induced mutations (27,92,113-114). These observations suggest that reduced metabolic intermediates may be the critical reactive electrophiles. 

Although 1-aminopyrene is a reduced metabolite of 1-nitropyrene, this arylamine will not covalently bind to DNA in vitro (72). In contrast, when incubations were conducted with the intermediate reduction product, N-hydroxy-l-aminopyrene, extensive covalent binding to DNA was detected (72). This observation is consistent with the previous report that several N-hydroxy arylamines formed DNA adducts and induced mutations in S. typhimurium (116), and suggests that, at least for 1-nitropyrene, reduction to N-hydroxy-l-aminopyrene is a critical step in mutation induction. 

Recently, Bryant t al. (70) examined the metabolism of 1,8-dinitropyrene in several S. typhimurium strains and found reduction to l-amino-8-nitropyrene and 1,8-diaminopyrene. In addition, other unidentified metabolites were detected in strains which were sensitive to 1,8-dinitropyrene-induced mutations (TA98 and TA98NR) but not in the resistant strains, TA98/1,8-DNP and TA98NR/1,8-DNP6. 

Certain nitro PAHs appear to require metabolism of their N-hydroxy arylamine derivatives in order to induce mutations. For example, while 2-nitrofluorene showed decreased mutagenicity in the nitroreductase-deficient mutant, TA98NR, and in strain TA98/1,8-DNP, its presumed ultimate mutagenic derivative, N-hydroxy-2-aminofluorene was inactive in only strain TA98/1,8-DNP (117). Observations such as these led McCoy t al. (117) to... 

Kobayashi S, Goto-Yamamoto N and Hirochika H. 2004. Retrotransposon-induced mutations in grape skin color. Science 304 982. 

Mutagenicity tests are usually carried out in vitro and in vivo, often using both prokaryotic and eukaryotic organisms. A well-known example is the Ames test, which assesses the ability of a drug to induce mutation reversions in E. coli and Salmonella typhimurium. 

Organic tin compounds have the effects of neurotoxicity, immunotoxicity and genotoxicity however, studies on the genotoxicity of organic tin compounds are comparatively scarce. It is important to study the genotoxicity of organic tin compounds, because those that show genotoxicity have the potency to induce mutations or cancer. 

Research on radiation-induced recessive lethal mutations — the predominant type of radiation-induced mutation — and dominant mutation systems (Sankaranarayanan 1991c)... 

Sankaranarayanan, K. 1991a. Ionizing radiation and genetic risks II. Nature of radiation-induced mutations in experimental mammalian in vivo systems. Mutat. Res. 258 51-73. 

Thacker, J. 1990. Molecular nature of ionizing radiation-induced mutations of native and introduced genes in mammalian cells. Pages 221-230 in Ionizing Radiation Damage to DNA Molecular Aspects. Proceedings of a Radiation Research Society — UCLA Symposia Colloquium. Lake Tahoe, CA, January 16-21, 1990. Wiley-Liss, New York. 

---