Mutagenicity obtained experimentally by oral administration of dextroamphetamine sulphate to the rat

Sections

Summary
Introduction
Materials and methods
Results
Discussion
Conclusions

Details

Author: Asdrubal LAREZ, , Esperanza BRICENO,, Yandyra OCHOA,, Martha MONTENEGRO, , Napoleón APONTE,
Pages: 67 to 70
Creation Date: 1979/01/01

Mutagenicity obtained experimentally by oral administration of dextroamphetamine sulphate to the rat

Asdrubal LAREZ, Chair of Toxicology,
Esperanza BRICENO,
Yandyra OCHOA,
Martha MONTENEGRO,
Napoleón APONTE,
Faculty of Pharmacy, Universidad Central de Venezuela, Caracas

Summary

Research work on the possible mutagenic effects of the amphetamine, sympathomimetic amine, was carried out on the rat. The method used was the dominant lethal assay, in its sub-acute form. Dextroamphetamine sulphate was administered orally. At the dosage and frequency of the test, dextroamphetamine sulphate was found to be a significantly mutogenic agent. The over-all mutagenic index was 13.92 per cent (P < 0.01) for the test group and 8.90 per cent for the control group.

Introduction

Research work aimed at determining the mutagenic potential of amphetamine, a sympathomimetic, psycho-stimulating medicament which is frequently abused for reasons of doping and drug dependence and suppresses fatigue and hunger, was carried out on the rat; the reasons for suspecting the existence of such potential being the possible correlation of amphetamine's teratogenic effect with high foetal reabsorption rates found in mice by some authors [ 2] , [ 9] and also its demonstrated gonadal effect with obvious spermatogenic changes in rats [ 11] .

Our purpose is to draw attention, with a view to promoting research in this new field of toxicology, to the need for compulsory checking of chemical substances which form part of man's environment and activity and which have not been tested in this type of research, so as to determine the possible genetic danger for future generations of many of these chemical substances, administered at a particular dosage and frequency.

According to Frohberg [ 6] , approximately 80 per cent of all mutations detected in humans cause the teath of the embryo [ 5] . It is for this reason that in our research we have selected the dominant lethal assay whereby effects fatal to the embryo can be detected experimentally [ 12] .

Materials and methods

The method used for this study was that of the dominant lethal assay in its sub-acute form [ 3] , which is widely recommended by many authors [ 2] , [ 4] , [ 6] . All genome and chromosome mutations which cause the death of t heir carriers during development of the embryo [ 10] can be detected with this test.

In order to perform the test, we administered, orally by tube, 2 mg/kg (onefifth of LD 50) of dextroamphetamine sulphate to a group of eight Sprague Dawley male rats aged 3 1/2 months and weighing between 300 and 350 g for five successive days. In the case of the control group of 10 rats with the same characteristics as the test group, only the solution of the medicament (physiological solution) was administered. Immediately afterwards, all the animals were mated for a period of five successive weeks, each male rat being mated every week with three female virgin rats aged between 2 and 3 months.

The females were sacrificed by ethyl ether and then autopsied on the fourteenth day of pregnancy, which was determined, using the vaginal smear method [ 1] , by the presence of spermatozoa in the rat's vagina on the day following the night-time mating with the male. The vital signs of the foetuses were noted and a calculation made of implants and reabsorptions, using the Salewski method, and the corpora lutea count [ 13] .

Results

The results were processed statistically, using the method of binomial distribution of proportions and percentages [ 7] . The over-all and weekly mutagenic index, expressed as a percentage of the number of early foetal deaths in relation to total implants, was established [ 2] , [ 8] , and is shown in tables 1 and 2 below.

TABLE 1

 

Evaluation of over-all mutagenic index

Group of rats

Number of pregnant rats

Total implants

Number of early foetal deaths

Mutagenic index in percentage

P

Control group
101 999 89 8.90
-
Test group
88 912 127 13.92
<0.01

TABLE 2

Evaluation of weekly mutagenic index

 

Mutagenic index in percentage

 

Week

Control

Test

P

1 10.44 14.36
>0.05
2 11.16 16.74
?0.05
3 11.21 19.58
<0.01
4 7.90 12.76
?0.05
5 4.78 7.02
>0.05

Discussion

  1. On the basis of the results shown in table 1, it can be established that, administered orally and at the dosage and frequency of the test, dextroamphetamine sulphate is a significantly mutagenic agent.

  2. The mutagenic effect begins to become apparent after the second week, is unmistakable in the third week and then declines in the following two weeks.

  3. Even though the phase of spermatogenic mitosis at which the damage occurred was not determined, it is obvious that there is damage in one such phase for at least one cycle of spermatogenesis, which can be completed in the five weeks of male rat sexual activity during mating.

  4. Since with the test methodology it is only possible to predict the type of mutation of chromosome aberrations (breaks, distortion and reduction in size) [ 8] , dextroamphetamine sulphate can be classified as a mutagenic agent of this type, manifestations of its activity ranging from death to abnormal development of offspring [ 8] .

Conclusions

From the results it is possible to conclude that dextroamphetamine sulphate, in the dosage and in the manner of administration tested, is a potentially mutagenic compound in the Sprague Dawley rat.

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