GENOTOXIC PYRROLIZIDINE ALKALOIDS AND PYRROLIZIDINE ALKALOIDN-OXIDES—MECHANISMS LEADING TO DNA ADDUCT FORMATION AND TUMORIGENICITY

Abstract

Plants that contain pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides are widely distributed in the world. These plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Although pyrrolizidine alkaloids have been shown to be genotoxic, including tumorigenic in experimental animals, the mechanisms of tumor formation have not been fully understood. Our recent studies on riddelliine, riddelline N-oxide, and dehydroretronecine (DHR) provided evidence suggesting that pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides induce tumors via a genotoxic mechanism, and that tumorigenicity is mediated by a set of eight DHR-derived DNA adducts. This mechanism may be general to other carcinogenic pyrrolizidine alkaloids and may also be responsible for the other genotoxicities of pyrrolizidine alkaloids, including mutagenicity and teratogenicity. It is hypothesized that these DHR-derived DNA adducts are potential biomarkers of pyrrolizidine alkaloid tumorigenicity. 353

Genotoxic Pyrrolizidine Alkaloids — Mechanisms Leading to DNA Adduct Formation and Tumorigenicity

“…Using riddelliine as an example, the metabolic pathways are shown in Figure 2. It was reported in our laboratories that rat and mouse liver microsomal metabolism of riddelliine produced riddelliine N-oxide and 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) as major metabolites and retronecine as a minor metabolite [15,19,40]. Dehydroriddelliine was presumably formed which upon hydrolysis produced DHP.…”

“…Like most of the genotoxic compounds, pyrrolizidine alkaloids require metabolic activation in order to exert genotoxicities [2,3,19,. During the last several decades, metabolism of pyrrolizidine alkaloids has been extensively studied both in vitro and in vivo .…”

“…Pyrrolizidine alkaloids, including clivorine, heliotrine, lasiocarpine, senkirkine, retrorsine, seneciphylline, and riddelliine, were found to be mutagenic in Salmonella typhimurium TA100 in the presence of the S9 activation enzyme system [3,19,27]. Pyrrolizidine alkaloids induce sister chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells [3].…”

Historical Overview of Chemical Carcinogenesis

“…In most cases, the rings are linked by a highly substituted diester group. Monoesterified PAs generally exhibit lower toxicity than PAs with a diester function, such as monocrotaline, riddelliine, and retrosine (Mattocks 1986;Fu et al 2001). PAs exhibit a range of genotoxic effects that include binding to DNA, cross-linking DNA, cross-linking proteins to DNA, mutagenicity, and carcinogenicity .…”

Low doses of monocrotaline in rats cause diminished bone marrow cellularity and compromised nitric oxide production by peritoneal macrophages

“…The finding of induced alterations in bone marrow cellularity in rats that received the 3.0 mg MCT/kg dose is not completely unexpected. The biotransformation of MCT by hepatic microsomal P450 3A (Kasahara et al, 1997) into the highly reactive metabolite MCTP results in increased DNA binding, DNA cross-linking, and DNAprotein crosslinking events (Petry et al, 1984;Hincks et al, 1991;Kim et al, 1993;Pereira et al, 1998;Fu et al, 2001), all of which can readily lead to a cell attaining an anti-mitotic state. This anti-mitotic property of MCTP is shared by the pyrrole metabolites of other pyrrolizidine alkaloids such as indicine-N-oxide (contained in Heliotropium indicum L. [a plant in Boraginaceae family]) that is administered to patients with leukemia and solid tumors (Poster et al, 1981;Whitehead et al, 1990).…”