Genotoxicity of pyrrolizidine alkaloids

Abstract

Pyrrolizidine alkaloids (PAs) are common constituents of many plant species around the world. PA-containing plants are probably the most common poisonous plants affecting livestock and wildlife. They can inflict harm to humans through contaminated food sources, herbal medicines and dietary supplements. Half of the identified PAs are genotoxic and many of them are tumorigenic. The mutagenicity of PAs has been extensively studied in different biological systems. Upon metabolic activation, PAs produce DNA adducts, DNA cross-linking, DNA breaks, sister chromatid exchange, micronuclei, chromosomal aberrations, gene mutations and chromosome mutations in vivo and in vitro. PAs induced mutations in the cII gene of rat liver and in the p53 and K-ras genes of mouse liver tumors. It has been suggested that all PAs produce a set of (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine-derived DNA adducts and similar types of gene mutations. The signature types of mutations are G : C --> T : A transversion and tandem base substitutions. Overall, PAs are mutagenic in vivo and in vitro and their mutagenicity appears to be responsible for the carcinogenesis of PAs.

Figure 1.

Schematic structure of pyrrolizidine alkaloid.

Figure 2.

Structures of representative carcinogenic pyrrolizidine alkaloids.

Figure 3.

Metabolism of pyrrolizidine alkaloids.

Figure 4.

Mutant frequencies induced by riddelliine in liver of female transgenic Big Blue rats. The upper panel shows mutant frequencies induced by riddelliine treatment in the cII genes in rat liver as a function of dose. The lower panel compares mutant frequencies with other biological consequences after riddelliine treatments in rat liver hepatocytes (solid bars) and endothelial cells (open bars). Data are from the literature (Chou et al., 2003c; Hirono et al., 1978; Mei et al., 2004a).

Figure 5.

Postulated mechanism of pyrrolizidine alkaloid carcinogenesis.