Mutagens relative mutagenic efficiency

Equations (45) and (47) give the integral yields for the case (Lk,Qm), These integrals will be of interest in defining relative mutagenic efficiency. 

High-surface-area polymers can be used to accumulate large amounts of relatively insoluble organic compounds from very large volumes of water. In the adsorption step of the accumulation, the more soluble components are not recovered efficiently so that the accumulated solutes do not accurately reflect the proportions of different compounds present at trace levels in the water. Nevertheless, the very simple polymer approach can be used for many studies because the mutagenicity appears to reside in the hydrophobic fraction that the polymers accumulate efficiently. This conclusion is based on favorable bioassay comparison of the extracts accumulated by the XAD-2 method and the extracts collected by the more complicated and expensive freeze concentration method (216, 233). 

The deamination or action of nitric oxide on guanosine gives xanthine (X) (91), which is a mutagenic lesion. dX had been assumed to be an unstable lesion, but has been shown to be relatively stable when present in a duplex at pH 7, though depurination occurs at pH < 4. In a template, HIV-RT incorporated dCTP and dTTP opposite dX with equal efficiency, whilst Kle-now fragment (exo-) preferentially incorporated dCTP. 7-Deaza-dX has also been prepared and incorporated into ODNs. ... 

Polymerase bypass of the mutagenic lesion 8-oxo-G has been studied in considerable detail. All DNA polymerases studied to date insert either dCTP or dATP opposite 8-oxo-G [82-90], Relatively modest decreases in catalytic efficiency have been observed for some polymerases (e.g., around 30-fold decrease for E. coli Pols I and II (exo ), around 10-fold for calf thymus Pol 8), whereas the catalytic efficiency of the model B-family polymerase from bacteriophage T7 (Pol T7) was inhibited around 270-fold as judged by pre-steady-state measurements [83, 85, 86, 91, 92], Only the Y-family polymerases Pol T (from Saccharomyces cerevisiae) and... 

The extreme level of BF inhibition is in contrast to steady-state analysis of human Pol 8. The degree of inhibition by 06-MeG observed for both the replicative Pol 8 (with the sliding clamp) and three recombinant Y-family polymerases (T, I, and k) was found to be relatively modest (10- to 100-fold) [149], With one exception, all of the human enzymes tested in the aforementioned study incorporated dCTP and dTTP equally well opposite 06-MeG. The exception to this pattern was human Pol t, which performed insertion of dTTP opposite 06-MeG 10 times better than dCTP opposite the lesion and with greater efficiency than dCTP opposite G (around 2-fold). It is entirely possible that inclusion of accessory proteins and/or post-translational modifications to the Y-family members could influence the catalytic efficiency of (/ -MeG bypass. In vitro studies with all polymerases studied to date verify the mutagenic potential of the 06-MeG adduct. 

Platinum compounds without antitumor activity (17) such as t2 ons-DDP and [Pt(dien)Cl]Cl (Figure 1) covalently bind to DNA in vivo. Several studies have compared the biological effects which result when equal amounts of these three platinum compounds are fixed on DNA (typically r j 10" -10"6), Cis-DDP is 5-10 times more toxic toward E, ooli ( ) and mammalian cells (j, U.) than t2 ans-DDP, The relative toxicity is correlated with the ability of these two isomers to inhibit DNA replication (, i3, J 4). The ois isomer is repaired more efficiently by E, ooli W and is at least 750 times more mutagenic in mammalian cells (11) than the trans isomer. The compound [Pt(dien)Cl]Cl binds covalently to the DNA of E, ooli and seems not to be repaired nevertheless this compound does not inhibit DNA synthesis or kill the bacteria ( ), Repair of platinum compounds by E, ooli may be under the control of the SOS system c s-DDP induces 5-10 times more recA protein in treated E. Coli than an equal amount of trans-DPP or [Pt(dien)Cl]Cl fixed on the DNA (18), It seems that different modes of fixation on DNA are responsible for the different mutagenicity, toxicity and DNA repair of these platinum complexes. These results suggest that the antitumor activity of platinum(II) compounds may also depend on the formation of particular platinum-DNA lesions. 

If the process of lipid peroxidation continues unimpeded, the consequences include the release of toxic breakdown products and the eventual destruction of the lipid component of biological membranes (S28). Such breakdown products include the aldehydes, malondialdehyde, 2-alkenals, and 4-hydroxyalkenals. A number of mammalian GST isoenzymes are highly efficient in the detoxification of these compounds (Dl). Indeed, 4-hydroxynonenal is one of the best GST substrates identified to date, and with one of the rat GST isoenzymes the K JK value obtained indicates that catalysis proceeds relatively close to the diffusion-controlled limit. Cholesterol-5,6-epoxide is a further example of a byproduct of lipid peroxidation, and the conjugation of GSH to this weakly mutagenic compound is catalyzed by certain GST (M18). 

Dhir, H., Roy, A.K., Sharma, A., 1993. Relative efficiency of Phyllanthus emblica fruit extract and ascorbic acid in modifying lead and aluminum-induced sister-chromatid exchanges in mouse bone marrow. Environ. Mol. Mutagen 21, 229—236. 

There may be a price to pay for the microorganism that dabbles in this chemistry. Those microbial strains that have an incomplete nitroreductase or a leaky enzyme that allows relatively high concentrations of nitrosoarene and arylhydroxylamine compounds to develop are subjecting the microbial population to toxic metabolites. On the other hand, perhaps the potential mutagenicity of these intermediates will contribute to the natural development of newer microbial strains that will more efficiently process these toxins in order to minimize autotoxicity. 

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