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Biomedical subjects

S P Pillai

Publications and source records attributed to S P Pillai.

9 recordsLinked to original sources

The ability of certain antimutagenic agents to prevent development of antibiotic resistance.

Resistance to multiple antimicrobial agents has now become a prominent fact of contemporary life. It is believed that poor patient compliance, e.g. interrupted or premature cessation of therapy; and misuse or abuse of antibiotics, e.g. wrong antibiotic or insufficient dose, play important roles in resistance development. We present evidence that, this form of resistance often stems from spontaneous mutations accompanied by the positive selecting pressure of the doses of antibiotics being between the MIC and MBC levels. A number of antimutagenic agents, e.g. green tea catechins, and other antioxidants, etc. are able to suppress the emergence of resistance. In many cases, these agents are capable of exerting these effects at doses which by themselves produce no visible effect on growth. In a number of cases antimutagenic substances capable of preventing resistance emergence are present in normal food stuffs. These effects are exerted against resistance to tetracyclines, fluoroquinolones, macrolides, beta-lactams, aminoglycosides and the like. The implications of these laboratory findings for practical chemotherapy are discussed.

Antimutagenic Agents↗

Role of antimutagens/anticarcinogens in cancer prevention.

Recently it has become increasingly clear that chemicals found in our foods and beverages can prevent the genetic damage that leads to cancer initiation. Such substances may also affect subsequent events in the pathways that lead to cancer, and may have the potential to inhibit the mutations that allow tumor cells to become resistant to antitumor agents. We describe here the antimutagenic potential of Glabrene analogs against EMS-induced mutations utilizing modified Ames tests in S. typhimurium TA 100 and E. coli JC 5088. Results of studies of the ability of well-known antioxidants such as EGCG and related compounds to prevent drug resistance mutations in microorganisms are described, and their possible significance in the prevention of chemotherapeutic drug-resistance in tumor cells is discussed.

Anticarcinogenic Agents↗

Multiple drug resistance.

Multiple drug resistance to antibacterial agents, antifungals, antivirals, antiprotozoals, and antitumor agents has risen spectacularly in the last decade or so and presently threatens eventually to put an end to successful chemotherapy in all of the above fields. This review summarizes the known origins of the problem, its present dimensions, the means employed to combat the phenomenon and promising avenues for future developments.

Animals↗

Structure-antimutagenic activity relationship study of plicatin B.

A systematic structure-activity relationship study of plicatin B (1), an antimutagenic constituent of Psoralea juncea, was undertaken with a view toward elucidating its chemical mode of action and possibly optimizing its antimutagenic activity during the process. Compound 1 and its related analogues were examined for their antimutagenic activity against mutations induced by ethyl methanesulfonate, a direct acting mutagen and alkylating agent, in Salmonella typhimurium strain TA100, utilizing the modified Ames test protocol. The dihydro analogue 3 resulting from saturation of the conjugated alkene double bond of 1 was found to exhibit reduced cytotoxicity and enhanced efficacy relative to the parent compound. This result serves preliminarily to exclude a Michael acceptor role of the alpha,beta-unsaturated carbonyl moiety in connection with its antimutagenic activity.

Acrylates↗

Umbelliferone analogues and their potential to inhibit Benzo(a)pyrene- and hydrogen peroxide-induced mutations.

Following the natural product lead, farneciferol-D (kopetdaghin, 8), some ether analogues of umbelliferone were synthesized and assayed for their potential to be antimutagenic/anticarcinogenic against mutations induced by benzo(a)pyrene, a potent mutagen/carcinogen, and hydrogen peroxide, and for their ability to function as free radical scavengers. The "true" antimutagenic effect of these compounds was determined at half the nontoxic concentration in Salmonella typhimurium strains utilizing a modified Ames test protocol, and their free radical-scavenging ability was assayed utilizing a nonenzymatic phenazine methosulfate (PMS)-NADH system. Umbelliferone analogues 4 and 5 demonstrated good potential in preventing mutations induced by benzo(a)pyrene and hydrogen peroxide and also exhibited good superoxide scavenging ability in the PMS-NADH assay, suggesting that the antimutagenic activity of these analogues may be linked to their antioxidative properties.

Antimutagenic Agents↗

Antimutagenic/antioxidant activity of green tea components and related compounds.

The ability of green tea components and other antioxidant compounds to function as antimutagens/antioxidants has been well established, and their role in cancer prevention is supported by numerous epidemiological studies. We have utilized modified Ames tests, superoxide scavenging assays, and assays for protection against DNA scissions to compare and contrast the protective effects of various teas and commercial and laboratory-isolated tea components to those produced by compounds such as resveratrol, selenium, curcumin, vitamins C and E, quercetin dihydrate, sulforaphane, ellagic acid dihydrate, glutathione reduced, trolox, butylated hydroxanisole (BHA), butylated hydroxytoluene (BHT), and N-acetyl-L-cysteine (NAC). In Ames tests, employing hydrogen peroxide as a mutagen, epigallocatechin gallate (EGCG) produced the highest level of protection of all antioxidants tested. Measurement of protection against DNA scissions produced results that again showed that EGCG produced the strongest protective effects. In scavenging assays using a xanthine-xanthine oxidase (enzymatic system), epicatechin gallate (ECG) showed the highest scavenging potential. In a nonenzymatic (phenazine methosulfate-NADH) oxidizing system, EGCG once again showed the strongest effects. The implications of these and similar results are discussed in relation to cancer prevention and prevention of drug/antibiotic resistance.

Antimutagenic Agents↗

Effects of antimutagens on development of drug/antibiotic resistance in microorganisms.

The effects of polyamines and related compounds on the development of drug/antibiotic resistance in a variety of bacterial strains were studied. Methods employed included standard toxicity assays, modified Ames tests for mutation frequencies and antimutagenic effects, prophage induction assays, and recA-lacZ and ada-lacZ induction assays. Using these methods, we have shown that the polyamines produce strong antimutagenic effects against EMS and MMS-induced antibiotic resistance. Spermidine also seems to have antimutagenic potential against 4NQO-induced mutations. DNA fidelity assays suggest that polyamines play a vital role in DNA synthesis, and several polyamines prevent the development of resistance to dihydrostreptomycin. The polyamine putrescine appears to be required for streptomycin action and also enhances the activity of some antibiotics (e.g., neomycin, kanamycin) but shows no enhancing effect on tetracycline or erythromycin. The potential significance of these studies for infectious diseases and tumor therapy is discussed.

Antimutagenic Agents↗

Polyamines and their potential to be antimutagens.

In order to determine the antimutagenic potential of polyamines, modified Ames tests were performed. Polyamines spermine, spermidine and putrescine all showed antimutagenic potential against EMS-induced reversions. In addition, the polyamines spermidine and putrescine showed potential to reduce the number of spontaneous revertants in modified Ames tests. Since spermidine and putrescine have the potential to reduce spontaneous mutations, we decided to perform DNA fidelity assays. DNA fidelity assays confirmed that putrescine has the potential to reduce the mutation frequency. However, spermidine had no effect. This suggests that putrescine may play a vital role in DNA synthesis and possibly be the active compound that plays a role in affecting EMS-induced mutations in the modified Ames tests. This is possible since all cells have the potential to convert spermine and spermidine to putrescine. However, since the DNA fidelity assay is an in vitro assay, the enzymes required for the conversion of spermine and spermidine to putrescine are absent. The possibility of conversion and the rate of conversion need further study.

Antimutagenic Agents↗