Fragile site analysis: its significance in environmental mutagenesis.
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Animals↗
Biomedical subjects
Y R Ahuja
Publications and source records attributed to Y R Ahuja.
Genotoxicity evaluation of the tricyclic antidepressants amitriptyline and imipramine using human lymphocyte cultures.
Two tricyclic antidepressants, amitriptyline and imipramine, were evaluated for their in vitro cytogenetic effects in human lymphocyte cultures. Peripheral blood cultures from three normal healthy donors were set up for 72 hr for each of the drugs. The drugs were added at the start (72-hr exposure), 24 hr (48-hr exposure), and 48 hr (24-hr exposure) after initiation of the cultures. The concentrations evaluated at each exposure time were 50, 250, 1,000, and 10,000 ng/ml for amitriptyline and 25, 500, and 5,000 ng/ml for imipramine. The first two concentrations correspond to the plasma levels of the respective drugs after therapeutic doses. All treatments for a donor were given at the same time. Untreated cultures served as controls for the baseline frequency of the parameters assayed. The parameters assayed were chromosome aberrations, mitotic index, and sister chromatid exchanges (SCEs). Amitriptyline was found to be nongenotoxic at plasma levels by all the parameters assayed. However, frequencies of chromosome aberrations and SCEs were significantly increased at concentrations 4 and 40 times the plasma level (1,000 and 10,000 ng/ml) although the actual increases was small. The mitotic index was not affected at any concentration. Through imipramine showed a significant increase in chromosome damage at the upper plasma level and at concentrations higher than that, SCE frequency was significantly increased only at concentration higher than the plasma level (5,000 ng/ml), the actual increase being small for both these parameters. The mitotic index was not affected at any concentration. These results suggest that amitriptyline may be a slightly safer drug than imipramine from a genetic point of view.
Amitriptyline↗
Folate deficiency induced chromosomal lesions in cancer patients.
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Chromosome Aberrations↗
Cytogenetic effect of neomycin on human lymphocytes in vitro.
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Cell Cycle↗
Down's syndrome in Hyderabad, India.
A cytogenetic analysis of Down's syndrome revealed straight trisomy 21 in 96.5 per cent affected. Remaining 3.5 per cent were found to have chromosomal mosaicism. In addition, a normal karyotype was observed in 2 individuals with Down's phenotype. A survey of Down's syndrome in Hyderabad gave an incidence of 1.17 per 1000 or 1 in 853 live births. There was a significant increase in the mean maternal age of the affected over the controls. Sex ratio was also higher in our sample of Down's syndrome as compared to the general population.
Adult↗
Genetic effects of drug interaction in tuberculosis patients and their fate.
In this paper we will discuss the genetic consequences of drug interaction in tuberculosis patients. Blood from tuberculosis patients was cultured before, during, and after withdrawal of therapy involving five different drug combinations of isoniazid (INH), thiacetazone (TAZ), para-aminosalicylic acid (PAS), and streptomycin (SM). The approaches used to detect DNA damage were chromosome aberrations and sister chromatid exchanges (SCEs). A total of 179 subjects were analyzed. In combination these drugs showed synergistic, additive, and antagonistic effects, though they were found to be nonclastogenic individually. Four of the drug combinations, INH + TAZ, INH + PAS, INH + TAZ + SM, and INH + PAS + SM, induced a significant increase in the frequency of aberrations, whereas INH + SM did not induce aberrations. In fact, SM appeared to reduce the frequency of aberrations. SCEs were increased in only two patients: one treated with INH + TAZ and the other with INH + PAS. The frequency of aberrations after withdrawal of therapy was decreased; it was slightly higher than the controls, though it was insignificant. The return to normalcy could be due to elimination of damaged cells or the repair of DNA in lymphocytes. Though the drug-induced aberrations do not persist after withdrawal of therapy, the chromosome damaging combinations of drugs should be used with caution, because the possibility of meiotic chromosome damage in germ cells (during therapy), which might be passed on to the next generation, cannot be ruled out.
Aminosalicylic Acid↗
Evaluation of genotoxicity of ampicillin and carbenicillin on human lymphocytes in vitro: chromosome aberrations, mitotic index, cell cycle kinetics, satellite associations of acrocentric chromosomes and sister chromatid exchanges.
A large number of drugs have been introduced into man's environment in recent years, many of which have been shown to have mutagenic, teratogenic and carcinogenic effects. Keeping in view the potential hazardous effects of drugs and chemicals, it is desirable to test new drugs for their genotoxic effects prior to widespread use. In the present investigation genetic effects of ampicillin and carbenicillin were studied in vitro in human lymphocytes using a number of end-points. These drugs were added at a range of concentrations and times during a 72h culture period. Concentrations corresponding to the plasma level after receiving therapeutic doses as well as concentrations higher than the plasma levels were examined. Neither drug affected the frequency of chromosome aberrations, satellite associations, mitotic index and cell turnover rate at plasma level concentrations. However, all these parameters were affected at higher concentrations. The frequency of SCEs was not increased with both the drugs irrespective of the concentrations or durations of treatment, suggesting that the mechanisms leading to the formation of SCEs and chromosome aberrations are different. Both ampicillin and carbenicillin were genetically non-toxic for the end points measured and non-clastogenic in vitro at therapeutic doses. However, previous studies have shown ampicillin to be clastogenic in vivo. For evaluation of genetic toxicity, drugs should be tested both in vitro and in vivo.
Adult↗
Combined and individual effects of isoniazid and thiacetazone on human lymphocyte chromosomes in vitro and in vivo.
Genetic effects of the drugs, isoniazid and thiacetazone used for antituberculosis chemotherapy were investigated on human lymphocyte chromosomes in vitro and in vivo. Therapeutic concentrations of these drugs did not induce chromosome aberrations in vitro both in combination and individually during any of the treatment period in 72 h lymphocyte cultures. At higher concentrations both the drugs were found to be cytotoxic. The frequency of chromosome damage was increased significantly in first-division metaphases of the patients, i.e. in vivo during treatment with isoniazid (300 mg) + thiacetazone (150 mg); this could be due to the synergistic action between the metabolites of the two drugs in the body or due to the metabolites of thiacetazone since isoniazid was found to be nonclastogenic in vivo. The frequency of sister chromatid exchanges was not increased in any of the patients except in one, who probably had a higher baseline level. These results suggest that chromosome aberrations and sister chromatid exchanges represent two different lesions. Chromosome damage induced by drugs could lead to congenital malformations, cancer, ageing and therefore contributes to the overall toxicology of the drugs and hazard to human genetic health. Hence drugs like isoniazid and thiacetazone which induce chromosome damage, should be used with caution.
Cell Division↗
Cytogenetic effects of psychotropic drug haloperidol on human lymphocytes.
Haloperidol is used for long-term therapy of psychiatric disorders. The cytogenetic effect of this drug was studied on human chromosomes in lymphocyte cultures in vitro and in vivo. There was no increase in the chromosomal aberration frequency in vitro with haloperidol at concentrations equivalent to plasma level and slightly higher than plasma level. However, a significant increase in the frequency of chromosome aberrations was seen in patients on therapeutic doses of haloperidol as compared to the two types of controls: 1. Psychiatric patients before starting the drug therapy and 2. normal healthy individuals from the general population. The most frequently observed aberrations were chromatid gaps and breaks. Our study indicates that haloperidol is not clastogenic in vitro at plasma concentration but significantly clastogenic in vivo.
Adult↗
Cytogenetic effect of colistin on human lymphocytes in vitro: chromosome aberrations, sister chromatid exchanges, mitotic index, cell cycle kinetics, and acrocentric associations.
Colistin, a peptide antibiotic, was tested at three different concentrations--71, 142, and 214 units/ml. One hundred forty-two units per milliliter corresponds to the plasma level after receiving therapeutic dose. There was a dose-dependent increase in the frequency of chromosome aberrations irrespective of the duration of treatment (T0, T24, T48). This antibiotic decreased the mitotic index and delayed the cell turn over rate indicating inhibition of DNA synthesis by it. Inhibition of DNA synthesis probably results in increase in the frequency of chromosome aberrations. Frequency of satellite associations of acrocentric chromosomes was increased with increasing concentration of the drug, but the differences at three concentrations were not significant compared to controls. There was no increase in the frequency of SCEs at any concentration or duration of treatment compared to controls. It appears that colistin induces the type of lesions that lead to chromosome aberrations and not to SCEs.
Adult↗
Further study on the cytogenetic effects of combined chemotherapy with isoniazid and para-aminosalicylic acid on human lymphocytes in vivo: sister chromatid exchanges, chromosome aberrations in first-division metaphases, cell growth kinetics, and mitotic index.
Tuberculosis patients under therapy with the drug combination isoniazid (INH) and para-aminosalicylic acid (PAS) were screened to investigate the cytogenetic effects. Results were compared with those from the patient controls (ie, tuberculosis patients before starting drug therapy) and general controls (individuals from the general population). The induction of chromosome aberrations was homogeneous and increased significantly in all the drug-exposed patients, whereas the frequency of sister chromatid exchanges (SCEs) was increased only in one of them. These results indicated differences in the two processes: chromosome aberrations and SCEs. Patients under therapy exhibited no change in cell growth kinetics, but the mitotic index was slightly enhanced compared to patient controls. It is concluded that the drug combination of INH + PAS induces damage in lymphocyte chromosomes in vivo. Further studies should be carried out on germ cells.
Adolescent↗
Cytogenetic effects of chemotherapy with three combinations of anti-tubercular drugs involving isoniazid, thiacetazone, para-aminosalicylic acid and streptomycin on human lymphocytes: chromosome aberrations, sister chromatid exchanges and mitotic index.
Cytogenetic effects of three combinations of anti-tubercular drugs were evaluated on human lymphocytes in vivo and were compared with controls of two types: (1) newly diagnosed tuberculosis patients before starting therapy and (2) individuals from the general population. The drugs used were: isoniazid (INH), thiacetazone (TAZ), para-aminosalicylic acid (PAS), and streptomycin (SM). These drugs were tested in the following combinations: (a) INH + TAZ + SM, (b) INH + PAS + SM, (c) INH + SM. The frequency of chromosome aberrations was significantly increased in patients treated with both the triple drug combinations, i.e., with INH + TAZ + SM and INH + PAS + SM, whereas patients treated with INH + SM did not exhibit an increase in the frequency of chromosome aberrations as compared to the controls. Although both the triple drug combinations were clastogenic, none of the three drug combinations tested induced an increase in the frequency of sister chromatid exchanges (SCEs). In other words, the mechanisms leading to SCEs and chromosome aberrations may be different. SM appeared to depress the mitotic index in patients treated with INH + SM and INH + PAS + SM, though it was found to possess a mild anti-clastogenic effect. INH + TAZ + SM, on the other hand, enhanced the mitotic index. This enhanced mitotic index was probably due to the presence of TAZ.
Aminosalicylic Acid↗
Clastogenic effect of the psychotropic drug thioridazine on human chromosomes in vivo.
Thioridazine (Mellaril), a psychotropic drug belonging to the phenothiazine group of drugs, was evaluated for its in vivo clastogenic effect on human chromosomes in lymphocyte cultures. Lymphocyte cultures were set up with peripheral blood samples of psychiatric patients (diagnosis: schizophrenia, mania, manic depressive psychosis, acute psychotic episode) who were on therapeutic doses of thioridazine for over 4 weeks. Two sets of controls were used: (1) newly diagnosed psychiatric cases (same type as above) who were not yet under therapy and (2) healthy individuals from the general population. The chromosomal aberration frequency was found to be significantly increased in the patients exposed to this drug as compared to the two sets of controls. The results point to a clastogenic and mutagenic potential of thioridazine and warrent a more careful consideration of its use in medicine.
Adult↗
Effect of cephaloridine on human chromosomes in vitro in lymphocyte cultures.
Cephaloridine is a semi-synthetic broad-spectrum bactericidal antibiotic derived from cephalosporin C. The drug was tested for its clastogenic effects on human chromosomes in vitro at various concentrations and for various periods of treatment (24, 48, 72 h) in 72-h lymphocyte cultures. 2 concentrations of the drug used in the tests (20 and 60 micrograms/ml) were similar to those found in the plasma of individuals after receipt of therapeutic doses of 500 mg and 2 g, respectively. 2 other concentrations tested were either below (10 micrograms/ml) or above (120 micrograms/ml) the plasma level. Control cultures were set up simultaneously for each batch of experimental cultures. The aberration frequency was increased with increasing concentration of the drug, irrespective of the duration of the exposure. In other words, there was a dose-effect relationship. No increase in chromosomal aberrations was observed with lower doses of 10 and 20 micrograms/ml. Significant increases were seen with higher doses of 60 and 120 micrograms/ml. Aberrations were mostly of the chromatid type. The results show that cephaloridine is clastogenic at the upper levels of permissible therapeutic doses.
Adult↗
Low incidence of X-chromatin in congenital hypothyroidism.
Buccal smears of 5 female patients with hypothyroidism (3 with congenital hypothyroidism or cretinism and 2 with acquired type) were studied for X-chromatin. Very low incidence of X-chromatin positive cells (1.33%, 1.59% and 2.06%) was found in all the three cases with cretinism while the incidence was the same (15.0% and 15.61%) as in the control females (15.5%), in 2 cases with acquired hypothyroidism. Chromosome studies were carried out in two cases of cretinism. They had a normal karyotype, 46 XX.
Adolescent↗
Dermatoglyphic studies in congenital heart disease in India.
Finger, palm and toe prints of 91 patients (53 male and 38 female) with congenital heart disease (CHD) were compared with those of 100 control subjects (50 male and 50 female). The CHD group included tetralogy of Fallot (TF), patent ductus arteriosus (PDA), pulmonic stenosis (PS), atrial septal defect (ASD) and ventricular septal defect (VSD). The dermatoglyphic traits studied were finger tip patterns, palmar patterns, toe patterns, presence of accessory triradii, absence of c triradius, total finger ridge count, palmar ridge counts (a-b, b-c, c-d, a-d and t-d), main line index and pattern intensity index. When CHD was considered as a whole and when individual classifications of CHD were considered separately, significant differences from the controls were observed in some of the parameters. But, in general, the parameters showing significant differences were not the same from one category to next. However, one parameter stood out for its consistency. There was a considerable decrease in the t-d ridge count in all the categories of CHD studied, showing a distal displacement of the axial triradius to the t' position.
Adolescent↗
Combined action of isoniazid and para-aminosalicylic acid in vivo on human chromosomes in lymphocyte cultures.
Two antitubercular drugs, viz., isoniazid (INH) and para-aminosalicylic acid (PAS), in combination, were evaluated for their in vivo clastogenic effects of human lymphocyte chromosomes. Lymphocyte cultures from tuberculosis patients taking a therapeutic dose of INH and PAS for a period of not less than 3 months and from two sets of controls were used: (1) newly diagnosed tuberculosis patients who were not yet under therapy and (2) healthy individuals from the general population. Chromosome aberration frequency was very significantly increased in the patients exposed to combined INH and PAS therapy as compared with controls. The most frequently observed aberrations were chromatid breaks and gaps. Isoniazid, the major antituberculosis drug, has been reported not to be clastogenic by itself. However, we observed that the INH--PAS combination commonly used in therapy was clastogenic. From this observation it may be concluded that INH and PAS act synergistically in producing chromosomal aberrations.
Aminosalicylic Acid↗
Chromosome-damaging action of isoniazid and thiacetazone on human lymphocyte cultures in vivo.
Antitubercular drugs in general are given in various combinations, one being isoniazid and thiacetazone. In the present study, was evaluated the in vivo chromosome-damaging effects of a combination of these two drugs in 72 h lymphocyte cultures. Chromosome aberrations were significantly increased in the patients treated with INH and thiacetazone as compared with two types of controls: (1) tuberculosis patients before starting the drug treatment and (2) individuals from the general population. The most frequently observed aberrations were chromatid breaks and gaps. It has been shown that individually, isoniazid may not be clastogenic on human chromosomes in therapeutic doses. The effects of thiacetazone on human chromosomes are not known. Consequently, the enhancement in chromosomal aberrations in the drug-exposed patients may be due to a synergistic effect of isoniazid and thiacetazone or to the clastogenic effects of thiacetazone alone.
Adolescent↗