Springer Online Journal Archives 1860-2000
Summary Dose-response curves to seven mutagens (X, UV, NEU, NMU, NA, HF, DEB) have been determined for a diauxotrophic strain of Neurospora (38701 ad-3A, 37401 inos). The data have been discussed from two points of view: mutagen specificity, and the meaning of dose-response curves in mutation research. The main results are as follows. 1. If mutagen specificity is defined as an overall excess of one type of reversion over the other, then three mutagens (UV, NEU, NMU) are specific for the inositol-allele, and four mutagens (X, HF, NA, DEB) are specific for the adenine-allele. 2. For all mutagens, the degree of specificity is dose-dependent, for some of them (HF, NA, DEB) strongly so. This is due to the fact that in every case the two dose-response curves either converge (X) or diverge (UV, NEU, NA, HF, DEB): after NMU treatment, they first diverge and, at still higher doses, converge again. As a result, an excess of one reversion type at low doses becomes reduced (X) or amplified (UV, NEU, NA, HF, DEB) at higher doses or reaches a maximum at an intermediate dose (NMU). These observations make it imperative to assess degrees of mutagen specificity from a comparison between dose-response curves and not from the ratio of the two reversion types at an arbitrarily chosen dose. 3. X and HF (which probably resembles X in its mode of action) are the only mutagens that show marked specificity already at the lowest doses. We have interpreted this to mean that the X-ray “target”, i.e. the probability that a random hit anywhere in the genome will cause a reversion, is at least ten times as large for the adenine-allele as for the inositol-allele. This agrees roughly with the ratio between the spontaneous reversion frequencies. 4. For all other mutagens, specificity is greatly reduced or altogether abolished at the lowest doses. Even DEB, which at high doses may produce several hundred times as many adenine- as inositol-reversions, produces only a few times as many at very low doses or when given to a growing culture instead of to a suspension of conidia. We have interpreted this to mean that the two alleles offer the same or a very similar “target” to every one of these five mutagens. The specificities observed at higher doses do not, therefore, arise from specific reactions between mutagen and DNA but from specific treatment effects on later steps in the mutation process, e.g. repair or enzyme function. This conclusion is supported by the fact that mutagen specificity can be modified by genetic background or by experimental conditions before, during or after treatment. The practical significance of this conclusion lies in the possibility that some direction may be given to the mutation process without having to await the — very improbable — discovery of chemicals with specific effects on individual genes. 5. The kinetics of mutation induction varied between mutagens; they rarely were the same for the two reversion types and could be modified by experimental conditions. The curves relating reversion frequency to dose varied from less than linear to more than quadratic. In most experiments, the dose exponent was higher for the more frequent reversion type than for the less frequent one. Reasons are given for considering the dose-response curves as composite ones in which the one-hit kinetics of the primary reaction between mutagen and DNA is overlaid by the kinetics of treatment effects on cellular conditions relevant to the mutation process. The strong exponential component (e c·dose) found in some of the dose-response curves suggests, but does not prove, that exponential inactivation of a repair enzyme may be one of these components.
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