Oxidation of NADH by chloramines and chloramides and its activation by iodide and by tertiary amines

Irreversible oxidation of reduced nicotinamide nucleotides by neutrophil-de rived halogen oxidants (HOCl, chloramines, HOBr, etc.) is likely to be a hi ghly lethal process, because of the essential role of NAD(P)H in important cell functions such as mitochondrial electron transport, and control of the cellular thiol redox state by NADPH-dependent glutathione reductase. Chlor amines (chloramine-T, NH2Cl, etc.) and N-chloramides (N-chlorinated cyclope ptides) react with NADH to generate the same products as HOCl, i.e., pyridi ne chlorohydrins, as judged from characteristic changes in the NADH absorpt ion spectrum. Compared with the fast oxidation of NADH by HOCl, k approxima te to 3 X 10(5) M-1 s(-1) at pH 7.2, the oxidation by chloramines is about five orders of magnitude slower; that by chloramides is about four orders o f magnitude slower. Apparent rate constants for oxidation of NADH by chlora mines increase with increasing proton or buffer concentration, consistent w ith general acid catalysis, but oxidation by chloramides proceeds with pH-i ndependent kinetics. In presence of iodide the oxidation of NADH by chloram ines or chloramides is faster by at least two orders of magnitude; this is due to reaction of iodide with the N-halogen to give HOI/I-2, the most reac tive and selective oxidant for NADH among HOX species. Quinuclidine derivat ives (Q)V) like 3-chloro-quinuclidine and quinine are capable of catalyzing the irreversible degradation of NADH by HOCl and by chloramines; QN(+)Cl, the chain carrier of the catalytic cycle, is even more reactive toward NADH than HOCl/ClO- at physiological pH. Oxidation of NADH by NH,Br proceeds by fast, but complex, biphasic kinetics. A compilation of rate constants for interactions of reactive halogen species with various substrates is present ed and the concept of selective reactivity of N-halogens is discussed. (C) 2001 Academic Press.