Influence on DNA

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The phenethylisoquinoline alkaloids present in some members of the Lily family (Liliaceae) are known to be toxic. Wang and Wang457 have researched the activity of veratridine on rats. This alkaloid causes persistent opening of the voltage-gate Na+ channel and reduces its single-channel conductance by 75%. However, its toxicity is concentration dependent. The toxicity of iso-quinoline alkaloid berberine is low in concentrations 0.05% for living plant cells464. In these concentrations berberine did not kill onion, corn or broad bean cells, although it did reduce the growth rates of corn and bean. Moreover, in these concentrations berberine is used as a mobile apoplastic tracer. Sequential application of berberine hemisulphate and potassium thiocyanate to plant tissue affects crystal formation in unmodified walls and in the lumina of dead cells. However, berberine does not affect crystals in lignified and suberized cell walls464. Berberine was alone tested for possible genotoxicity, mutagenecity and recombinogenic activities in micro-organisms465. An SOS-chromotest with this alkaloid shows that there is no genotoxic activity nor significant cytotoxic, muta-genic or recombinogenic effects in in vitro (non-growing) conditions. However, Pasqual et al.465 have observed the metabolic activity of this alkaloid in dividing cells. It has induced important cytotoxic and cytostatic effects in proficient and repair-deficient Saccharomyces cerevisiae strains. According to Pasqual et al.465, berberine's cytotoxicity results from a mutational blockage in the DNA strand-break repair pathway (rad52-1). The influence of this alkaloid on DNA is evident. Pasqual et al.465 have observed the same cytotoxicity in a triple mutant blocked in the excision (rad2-6), in the mutagenic (rad6-1) and in the recombinogenic (rad52-1) repair pathways. Although this toxicity has been observed in dividing cells, Pasqual et al.465 concluded in their discussion of results that berberine is not a potent mutagenic agent although one cannot rule out possible implications of DNA topoisomerases in berberine toxicity mechanisms. The results presented by Pasqual et al.465 have sufficiently characterized the nature of alkaloid activity and its potential toxicity. These characteristics are also typical for other alkaloids in general, although there may be some exceptions and reservations. Figure 87 presents the acute toxicities of berberine and thebaine. These alkaloids are very selective in their toxicity. There are also strong differences in acute toxicities according to the form in which these alkaloids were administrated to mice.

o CO

LO.Q

O CS

Berberine, i.p.

—o—

Berberine, i.v.

Berberine, p.o.

—V—

Thebaine, i.p.

Thebaine, i.o

-0-

Thebaine, p.o.

Alkaloids

Figure 87. Acute toxicity of berberine and thebaine on mice in relation to form administration. Abbreviations: 1 - berberine; 2 - thebaine.; i.p. - intraperitoneal; i.v. - intravenous; p.o. - oral.

There are studies suggesting that nicotine influences human carcinogenesis. One such study was carried out by the Kleinsasser research group from the University of Regensburg in Germany466. To assess the genotoxicity of this alkaloid, researchers tested the DNA-damaging effect on human lymphocytes and target cells from lymphatic tissue. The experimental data by Kleinsasser et al.466 evidently indicated that nicotine significantly and directly causes geno-toxic effects in human target cells in vitro. However, there were no differences in DNA damage observed in cells from smokers and non-smokers incubated without nicotine. Kleinsasser et al.466 suggest that the lack of higher DNA damage in smokers compared to non-smokers is connected only with nicotine dose.

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