Acyl glucuronide reactivity in perspective: biological consequences

The metabolic conjugation of exogenous and endogenous carboxylic acid substrates with endogenous glucuronic acid, mediated by the uridine diphosphoglucuronosyl transferase (UGT) superfamily of enzymes, leads to the formation of acyl glucuronide metabolites. Since the late 1970s, acyl glucuronides have been increasingly identified as reactive electrophilic metabolites, capable of undergoing three reactions: intramolecular rearrangement, hydrolysis, and intermolecular reactions with proteins leading to covalent drug-protein adducts. This essential dogma has been accepted for over a decade. The key question proposed by researchers, and now the pharmaceutical industry, is: does or can the covalent modification of endogenous proteins, mediated by reactive acyl glucuronide metabolites, lead to adverse drug reactions, perhaps idiosyncratic in nature? This review evaluates the evidence for acyl glucuronide-derived perturbation of homeostasis, particularly that which might result from the covalent modification of endogenous proteins and other macromolecules. Because of the availability of acyl glucuronides for test tube/in vitro experiments, there is now a substantial literature documenting their rearrangement, hydrolysis and covalent modification of proteins in vitro. It is certain from in vitro experiments that serum albumin, dipeptidyl peptidase IV, tubulin and UGTs are covalently modified by acyl glucuronides. However, these in vitro experiments have been specifically designed to amplify any interference with a biological process in order to find biological effects. The in vivo situation is not at all clear. Certainly it must be concluded that all humans taking carboxylate drugs that form reactive acyl glucuronides will form covalent drug-protein adducts, and it must also be concluded that this in itself is normally benign. However, there is enough in vivo evidence implicating acyl glucuronides, which, when backed up by in vivo circumstantial and documented in vitro evidence, supports the view that reactive acyl glucuronides may initiate toxicity/immune responses. In summary, though acyl glucuronide-derived covalent modification of endogenous macromolecules is well-defined, the work ahead needs to provide detailed links between such modification and its possible biological consequences. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

Effects of artificial foods on the blood chemistry of the Australian magpie

Bird feeding on residential property is a popular activity throughout Western countries. Advocates insist the practice is beneficial, while opponents maintain that it can result in a wide range of negative outcomes including malnutrition. The biological effects of 'backyard feeding' were studied in Australian magpies Gymnorhina tibicen during the non-breeding season in 1999 in the Greater Brisbane and the Lockyer Valley regions, south-east Queensland, Australia. Six magpie populations were selected and 70 birds were individually tagged for identification. The birds were provided with processed foods, 20-40 g per bird daily. To monitor the effects of the food, blood chemistry and body mass (BM) were used as indices. Significant effects were observed in BM and plasma cholesterol (PC), showing strong sensitivity to food provisioning. Significant effects on PC and uric acid were found only when birds were fed dog sausage. Results suggest that blood PC levels in magpies are readily influenced by, probably, the lipids present in food, and that the type of food can affect blood PC levels. These effects may occur widely among fed magpies if the influence that we demonstrated at plasma level can be generalized. Following the free-ranging study, six magpies were captured and subjected to a 6-day captive experiment to determine whether the selected foods had the potential to alter the birds' blood chemistry. It was found that all of the foods, when provided ad libitum, influence at least two of the three blood parameters (PC and non-esterified fatty acids). Due to its popularity, wildlife feeding will continue. To make wildlife-feeding activities truly sustainable, there is a need for further studies. This study clearly demonstrated that the physiology of wild magpies can be affected by 'backyard feeding'.