Correlation of DNA damage in epidemic dropsy patients to carcinogenic potential of argemone oil and isolated sanguinarine alkaloid in mice

Abstract

In recent times, a higher incidence of gall bladder carcinoma in the Indo‐Gangetic basin has been linked with the consumption of contaminated mustard oil. Consumption of mustard oil contaminated with argemone oil (AO) is well known to cause clinical manifestation referred to as “epidemic dropsy.” Because sanguinarine, an active alkaloid of AO, has been shown to intercalate DNA, a possible correlation of DNA damage in epidemic dropsy patients to tumorigenic potential of AO and isolated sanguinarine alkaloid in mice was investigated in the present study. Single topical application of AO (0.15–0.3 ml) or isolated sanguinarine (4.5–18 μmol) followed by twice‐weekly application of tetradecanoylphorbolmyristate acetate (TPA) for 25 weeks resulted in formation of tumors. Histopathologically these tumors were of squamous cell carcinoma type and similar to those found in the positive control group using dimethylbenzanthracene (DMBA)/TPA. The activities of cutaneous γ‐glutamyl transpeptidase (GGT) and glutathione‐S‐transferase P (GST‐P), marker enzymes of tumorigenesis, were found to exhibit higher expression in AO or isolated sanguinarine/TPA treated groups when compared to control. The higher expression of p53 and p21/WAF1 in skin after single topical application of AO or isolated sanguinarine further confirms the tumorigenic response. Single topical application of AO or isolated sanguinarine alkaloid to mice showed significant DNA damage in terms of Olive tail moment (89–129%), tail length (54%) and tail DNA (153–205%) using Comet assay in skin cells. Further, the extent of DNA damage in blood cells of epidemic dropsy patients in alkaline Comet assay was found to be significantly higher as compared to normal population, indicating the genotoxic response of AO exposure. Although the genotoxic lesions may be repaired to some extent on withdrawal of consumption of AO contaminated mustard oil and the residual genotoxic effects caused by AO may not be expressed as signs of carcinogenesis. Environmental factors or hormonal changes during aging process may lead to stimulate/promote the genetically altered latent cells to form neoplastic lesions and can act as one of the etiological factors responsible for higher incidence of gall bladder carcinoma in the population of Indo‐Gangetic basin. © 2005 Wiley‐Liss, Inc.

Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives

“…It is a matter of fact, however, that sanguinarine has been listed as responsible for the toxicity of Argemone mexicana seed oil [100][101][102] . Das et al [103] reported that topical use of argemone oil (0.15-0.3 mL) or sanguinarine (4.5-18 μmol/L) followed by application of TPA induces tumor development in a murine experimental model. Ansari et al [104] also reported that intraperitoneal administration of sanguinarine induces DNA damage in Swiss albino mice.…”

“…Sanguinarine in argemone oil, is suspected to cause glaucoma [101,102] . Argemone oil increases incidence of bladder cancer in animal models [103] and of gall bladder cancer in humans [104] . Furthermore, sanguinarine extract from bloodroot (Sanguinaria canadensis), previously used in oral hygiene products, was discontinued until a link between product administration and occurrence of leukoplakia was established [105,106] .…”

Natural Products Modulate the Multifactorial Multidrug Resistance of Cancer

“…In addition, IQAs forms in vitro DNA adducts via modification of the C(11) = C(12) bond detectable by 32 P-postlabelling [186]. Although IQAs mediated DNA damage in vitro and in vivo has been published [187].…”

Effects of Sanguinarine and Chelerythrine on the Cell Cycle and Apoptosis

“…This observation is the basis for the conclusion 5 that the neutral form (pseudobase) of SA and CHE can interact with proteins, it is involved in the interactions with cellular biomacromolecules and may elicit a cytotoxic response 6 . SA and CHE forms in vitro DNA adducts via modification of the C (11) =C (12) bond (calf thymus DNA, rat hepatic microsomes, NADPH, pH 7.4) detectable by 32 P-postlabelling 7 .…”

“…The role of QBA in the genesis of epidemic dropsy syndrome (A. mexicana poisoning) has not been explicated to date 10 , although SAmediated DNA damage in vitro 11 ( Fig. 1) and in vivo [12][13][14] has been published. In studies focused on SA-mediated DNA damage in mice, the minimum genotoxically ef-…”