Further investigations of the role of acetylation in sulphonamide hypersensitivity reactions

Abstract

Sulphonamide hypersensitivity reactions are believed to be mediated through reactive intermediates derived from oxidation of the paraamino group to form sulphonamide hydroxylamines. Sulphamethoxazole hydroxylamine (SMX-HA) can be acetylated by N-acetyltransferase (NAT) enzymes to form an acetoxy metabolite (acetoxySMX). In the current studies, acetoxySMX was found to be not toxic over the concentration range of 0 to 500 μM towards a human lymphoblastoid cell line (RPMI 1788) or a human hepatoma cell line (HepG2). Further, transient expression of NAT1 in COS-1 cells or stable transfection of NAT1 andNAT2 in HepG2 cells did not alter the toxicity of SMX-HA in vitro. The activity of NAT1 in isolated mononuclear leucocytes (a reflection of systemic NAT1 activity) determined with paraaminobenzoic acid as a substrate was not different between controls (n = 11) or patients with a known hypersensitivity reaction (n = 5) (4.1 ±1.2 nmol min⁻¹mg⁻¹ vs 5.7 ± 1.4 nmol min⁻¹ mg⁻¹). Thus, acetoxy SMX is unlikely to play a significant role in mediating SMX hypersensitivity reactions anda constitutive deficiency in NAT1 activity is not a common finding in patients susceptible to SMX hypersensitivity reactions.

Key Words :

• Sulphamethoxazole
• hydroxylamine
• hypersensitivity
• N-acetyltransferase
• cytotoxicity