Drug reactions with aldehyde adducts as a novel route to protein haptenisation: Recent tentative clinical evidence for a role in hydralazine vasotoxicity

Some classic explanations for toxicities caused by small molecule drugs implicate reactive metabolites formed during processing by hepatic enzymes. Such metabolites can be deleterious if they evade detoxication and attack electron-dense amino acids to form adducts within cell proteins. Since such damage accompanies many idiosyncratic adverse drug reactions and other toxic outcomes, reducing tendencies for reactive metabolite formation is a key objective in modern drug discovery. Some 2 decades ago our laboratory identified an alternative route to drug-mediated protein modification that differs from conventional pathways yet could conceivably represent a plausible route to haptenization in vivo. Rather than the drug itself acquiring reactivity during metabolism, in this scenario the target protein first acquires a reactive centre via adduction with an endogenous bifunctional aldehyde. In a second obligatory step, a coupling reaction occurs in which an electron-rich drug attacks the activated protein to form a ternary drug-aldehyde-protein complex. Using acrolein as the coupling agent and the antihypertensive hydralazine as a model nucleophilic drug, we obtained strong in vitro and in vivo evidence for drug-aldehyde-protein coupling reactions, yet the potential clinical significance of these findings was not addressed. The possibility that drug-aldehyde-protein complexes could act as haptens to trigger autoimmune responses is suggested by a recent clinical study by Falk and associates which explored their possible contribution to hydralazine-associated ANCA vasculitis. This Review will explore the background to these findings and some possible hypothesised determinants of toxicity involving formation of aldehyde-coupled drug adducts.