The Reaction of Amines with Carbonyls: Its Significance in the Nonenzymatic Metabolism of Xenobiotics

Abstract

The studies cited above indicated that many carbonyl amine reactions can alter both in vitro and in vivo rates of xenobiotic metabolism. The carbonyl amine reaction may be enzymatic or nonenzymatic and in most instances is readily reversible with few examples of the isolation and identification of the Schiff bases (azomethine). Endogenous primary amine and amines generated by metabolic N-dealkylation can react with biogenic ketones and aldehydes and under selected physiological conditions give further condensation products. The new products in most instances alter the biological activity and/or toxicity. It is apparent that these findings can be extended to carbonyl hydrazine reactions. The rates of reaction for simple alkyl and aryl hydrazine are more rapid and the products of these reactions and more stable, with the condensation products of alpha-keto acids being isolated and characterized the most frequently. The further reaction of hydrazones to yield condensation products is also observed with selected hydrazines such as hydralazine. It is now clear that the inherent toxicity of many exogenous ketones and aldehydes exists. Many of these toxicities are due to the reactions which occur with the amino groups of amino acids and proteins. The condensation reactions in most instances are readily reversed and are only dependent on the physiological concentration of aldehydes of ketones. However, there are a number of ketones and aldehydes, some of which are metabolically produced that are capable of forming azomethine intermediates which are not readily reversed under physiological conditions. There are an increasing number of examples of further nonenzymatic condensations which result in stable products which can alter xenobiotic metabolism.

Biodegradable Gold Nanoclusters with Improved Excretion Due to pH-Triggered Hydrophobic-to-Hydrophilic Transition

“…3,3′-Dithiobis­(propanoic dihydrazide) contains two terminal hydrazide groups and an internal disulfide. Hydrazide was chosen as the aldehyde linking group, as opposed to a primary amine, because it is generally resistant to acidic hydrolysis, especially when it is further stabilized by reduction with cyanoborohydride. , After conjugation of the dihydrazide with two dextran molecules, the disulfide was reduced with tris­(2-carboxyethyl)­phosphine (TCEP) to yield dextran-thiol, which was isolated by washing in 90% methanol. Notably, disulfides are generally capable of binding gold surfaces without prior reduction; , however, we found that the dextran disulfide dimer could not be efficiently conjugated with gold, presumably due to steric occlusion.…”

Acrolein scavengers: Reactivity, mechanism and impact on health

“…It was reported to exert its vasodilatory action through direct relaxation of the vascular smooth muscle cells [89]. Some strong nucleophilic groups in its structure also render its possible scavenging capability of several biogenic ketones and aldehydes under certain physiological conditions [90]. In a model of ACR-modified BSA at neutral pH and 371C, hydralazine was found to attenuate the carbonylation level with better effects than other scavengers such as aminoguanidine and carnosine.…”

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 4. Reactions of Conjugation and Their Enzymes

“…In this last and short Chapter, we examine two unusual types of metabolic reactions, namely the nonenzymatic coupling of xenobiotic amines with endogenous carbonyl compounds [369]. The first type of reaction is covered in the present Figure and involves the condensation of xenobiotic hydrazines and hydrazides with an endogenous ketone or aldehyde to form a Schiff base called a hydrazone.…”