Inhibition of yeast alcohol dehydrogenase by dehydroretronecine

Pyrrolizidine Alkaloids: Metabolic Activation Pathways Leading to Liver Tumor Initiation

“…The reversibility of the secondary metabolites was first observed by Curtain and Edgar in 1976, who discovered that the binding of dehydroheliotridine (DHH) with DNA was reversible . In 1997, Sun et al determined that the binding of DHR with albumin was reversible, and in 1983, Mattocks and Bird determined that the reaction product of DHR and nicotinamide was also reversible The interconversion and the reversible reactions proceed through an SN1 mechanism, and the resulting carbonium ion can be stabilized by resonance…”

“…The reversibility of the secondary metabolites was first observed by Curtain and Edgar in 1976, who discovered that the binding of dehydroheliotridine (DHH) with DNA was reversible. 97 In 1997, Sun et al determined that the binding of DHR with albumin was reversible, 130 and in 1983, Mattocks and Bird determined that the reaction product of DHR and nicotinamide was also reversible 131 The interconversion and the reversible reactions proceed through an SN1 mechanism, and the resulting carbonium ion can be stabilized by resonance. 2 Partly based on these observations, Edgar et al proposed that, in vivo, DHP, DHP−DNA adducts, and DHP−protein adducts can be dissociated in the liver, resulting in pooled secondary metabolites and the formation of multiple activation pathways leading to PA-induced liver tumor initiation.…”

“…Partly based on these observations, Edgar et al proposed that, in vivo, DHP, DHP–DNA adducts, and DHP–protein adducts can be dissociated in the liver, resulting in pooled secondary metabolites and the formation of multiple activation pathways leading to PA-induced liver tumor initiation . Although this proposed mechanism is promising, the structures of the secondary metabolites described above have not been fully characterized. ,,, It is also not known whether these reaction products are indeed metabolites formed in vivo and whether they are involved in liver tumor initiation. As such, for the support of this proposed mechanism, it is timely and important to determine that some identified secondary metabolites can indeed undergo dissociation, interconversion, and reversible reactions.…”

Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease

“…Unlike the highly reactive DHP esters, the effects of which are largely if not entirely confined to the liver, , DHP survives for a longer time in the body . It escapes from the liver and has been isolated and identified in both in vivo and in vitro studies of dehydroPA metabolism. ,, While less chemically reactive than the precursor DHP esters, DHP retains significant bifunctional, biological alkylating potential, especially under mildly acid conditions, and, as with the DHP esters, it forms C7 and C9 DHP adducts in vivo (Figure ). ,,− DHP adducts have been detected in the liver, lung, kidney, blood, bone marrow, gastrointestinal tract, brain, muscles, pancreas, thymus, heart, spleen, and testes of animals exposed to dehydroPAs and following intraperitoneal or subcutaneous injection of DHP. ,,,,− …”

“…In accord with this, a mixture of preformed galectin-1-DHP adducts (Figure ), shown by mass spectrometry to be mainly monoadducted, was found to be cytotoxic in human pulmonary artery endothelial cells . More importantly, it has been established that some DHP adducts, involving DHP attached to weak nucleophiles, can dissociate and release DHP or transfer DHP to stronger nucleophilic sites. ,− , The in vivo persistence of “a reservoir of stabilized pyrrolic alkylating agents (DHP adducts) which could subsequently interact with other tissue constituents” is one reason why the toxic effects of dehydroPAs continue to develop slowly over an extended period even from a single exposure to these hazardous substances. ,− ,− , The reversibility of the reaction of dehydroPA metabolites with certain weak nucleophiles prolongs the effects and enhances the hazard of dietary exposure to dehydroPAs relative to some other genotoxic substances, and this fact should be taken into account in assessing the risk of foods contaminated by these alkaloids.…”