Cytotoxicity of Benzo[c]phenanthridinium Alkaloids in Isolated Rat Hepatocytes

Abstract

Sanguinarine, chelerythrine and fagaronine were examined for hepatotoxic effect. Administration of sanguinarine and chelerythrine (10 mg/kg/day; i.p.) produced marked parenchymal injury not found in the livers of fagaronine treated rats. In chronic administration of sanguinarine (0.2 mg/kg/56 days; i.p.) degeneration and necrosis were not observed in the liver. The effect of the alkaloids was tested by enzyme leakage (LDH and ASAT) and changes in glutathione levels in isolated rat hepatocytes. Sanguinarine produced the greatest toxicity followed by lesser toxicity in the case of chelerythrine while no toxicity was displayed with fagaronine. These effects correlate with pKR+ values for pseudobase formation. Finally, no increased lipid peroxidation or mitochondrial membrane damage were found.

Intracellular Accumulation as an Indicator of Cytotoxicity to Screen Hepatotoxic Components of Chelidonium majus L. by LC–MS/MS

“…Our results of the intracellular accumulation of sanguinarine, coptisine, and chelerythrineare are consistent with the hepatotoxicity data reported previously [18,23,24]. Also, sanguinarine produced greater toxicity than chelerythrine [25].…”

Chelerythrine-Induced Apoptotic Cell Death in HepG2 Cells Involves the Inhibition of Akt Pathway and the Activation of Oxidative Stress and Mitochondrial Apoptotic Pathway

“…Among these several alkaloids, sanguinarine, CHE, and coptisine were more toxic than the others, and these three compounds were also considered potential toxic compounds [ 14 ]. Ulrichova and colleagues showed that a signal dose of sanguinarine or CHE (i.e., 10 mg/kg/day) could cause acute necrosis in the liver tissues of rats [ 32 ]. It was also found that intravenous injection of CHE at a dose of 5 mg/kg could induce the production of ROS and apoptosis in the cardiac myocytes of rats [ 18 ].…”

Dual action anti‐inflammatory/antiviral isoquinoline alkaloids as potent naturally occurring anti‐SARS‐CoV‐2 agents: A combined pharmacological and medicinal chemistry perspective

“…The role of the hydroxyl functional group in reducing the toxicity and adverse effects of bioactive compounds. (a) The chemical structure of emetine and its hydroxyl‐containing analog cephaeline with less cytotoxicity (Ren et al, 2022); (b) The chemical structure of well‐known benzo[c]phenanthridine alkaloids chelerythrine and sanguinarine, and their liver‐safe analog fagaronine (Ulrichová et al, 1996); (c) The chemical structure of standard anti‐SARS‐CoV‐2 drug chloroquine and its safer analog hydroxychloroquine in terms of cardiotoxicity (Kamp et al, 2020). …”

“…For example, one study found that the presence of a hydroxyl group in the structure of fagaronine caused this alkaloid to be devoid of any hepatotoxicity at a single i.p. dose of 10 mg/kg, while its hydroxyl-free analogs (sanguinarine and chelerythrine) with the same benzo[c]phenanthridine backbone caused significant parenchymal damage to the liver cells (Figure 3b) (Ulrichová et al, 1996).…”

“…For example, one study found that the presence of a hydroxyl group in the structure of fagaronine caused this alkaloid to be devoid of any hepatotoxicity at a single i.p. dose of 10 mg/kg, while its hydroxyl‐free analogs (sanguinarine and chelerythrine) with the same benzo[c]phenanthridine backbone caused significant parenchymal damage to the liver cells (Figure 3b) (Ulrichová et al, 1996). Hydroxychloroquine which is a structural analog of chloroquine with similar therapeutic and pharmacokinetic properties has less toxicity than chloroquine and is better tolerated in patients, just due to having one more hydroxyl group (Figure 3c) (Colson et al, 2020; Gao & Hu, 2020).…”