Mutation-induction kinetics

In this chapter, we have set forth a formal mathematical description of mutation-induction kinetics on the basis of certain simplifying assumptions. The resulting equations are sufficient for the analysis of many dose-response relationships found for radiations and chemicals. From this base, more elaborate mathematical methods could be developed to deal with more complex experimental situations or macromolecular processes than we have considered here. 

Mutation yields, and in particular the position and magnitude of maximum yields, should be measured as carefully as possible as a means of verifying the apparent pattern of mutation-induction kinetics revealed in mutation-frequency curves. For purely linear mutation induction and exponential survival, the maximum mutant yield occurs at the LD37 dose for other nonlinear kinetic patterns, the position and magnitude of the maximum yield shift in mathematically predictable ways. For any given kinetic pattern of killing and mutation, the ratio of the maximum mutant yields plotted over lethal... 

Another important area of research is the modification of mutagenic activity. In the chapter by Sugimura and Nagao, factors that alter in vitro metabolic activation are discussed, whereas in the chapter by Maher and McCormick, the role of genetic heterogeneity is considered. Equally important is our need to obtain a better understanding of mutation-induction kinetics, and the mathematical analysis by Haynes and Eckardt provides an important step in this direction. An important new approach for the induction of specific locus mutations in human cells in culture is discussed in the chapter by Thilly and co-workers. 

Many mutagenic compounds are very labile under the treatment conditions used for the Neurospora conidia. Sometimes mutagens are used in such minute concentrations that the conidia will absorb a considerable amount of the compound from the solution e.g., 2 X 10 conidia will absorb 2.5 X 10" M ICR-170 (an acridine mustard derivative). These factors must be considered when the kinetics of the induced mutation frequency is measured as a function of increasing time. The mutation-induction curves... 

In Figure 7, we have plotted yet another similar set of data for ade2 forward mutations in a wild-type haploid strain. Again, the survival curve is biphasic LQk), and mutation induction is linear over an unusually wide range of dose. (A high dose decline in frequency probably occurs above 1000 ergs/ mm. ) For such a LQk,Lm) kinetic pattern, we would expect to find a yield curve with nonzero initial slope and a maximum at /2LD14 within the limits of the data, these expectations appear to be met. 

F. Eckardt and R. H. Haynes, Kinetics of mutation induction by ultraviolet light in excision-deficient yeast. Genetics 85, 225-247 (1977). 

B. B. Webber and F. J. deSerres, Induction kinetics and genetic analysis of X-ray induced mutations in the ad3 region of Neurospora crassa, Proc. Natl. Acad. Sci. U.S.A. 53, 430-437 (1965). 

The early studies of the kinetics of induction of recessive lethal mutations in Drosophila showed linearity at low doses and no evidence of a threshold. The contention that there is no threshold, or "safe" dose, has dominated genetic thinking on radiation effects and has carried over to chemicals. However, it was long assumed that carcinogenic effects of radiation and chemicals had a threshold. It may be helpful to review some of the recent studies of carcinogenesis. 

The uptake kinetics of C-labelled triadimenol, shown in figure 6 were examined in both the susceptible and triadimenol-resistant strains of the yeast Saccharomycopsis lipolytica. To minimize the effect of unspecific absorption on the cell surface the incubated cells were separated by suction filtration and washed twice with unlabelled triadimenol. The passive uptake curve shows the typical characteristics of saturation by diffusion, equilibrium being reached after about 20 minutes. There are no real differences between the susceptible and resistant isolates, and no indication of transport mutation or induction of efflux transport can be derived from these data. 

Studies with NR-deficient mutants, however, do not suggest a direct linkage between nitrate uptake and the soluble NRs. Mutations in the NADH NR and the NAD(P)H NR structural genes, resulting in the loss of NR activity and protein, had no effect on induction, rate, or kinetics of nitrate uptake in barley... 

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