Diamine oxidase as a plasma marker of rat intestinal mucosal injury and regeneration after administration of 1-beta-D-arabinofuranosylcytosine

Abstract

Diamine oxidase (DAO; EC 1.4.3.6) is an enzyme found in high activity in the mature upper villus cells of rat intestinal mucosa and only in very low activity in all other tissues except for the placenta in the pregnant rat. The present study was designed to investigate whether plasma and mucosal DAO could be used to monitor the timing and severity of injury and recovery of the intestinal mucosa after administration of the chemotherapeutic agent 1-beta-D-arabinofuranosylcytosine (ara-C). A dose of 0.3 g/kg s.c. every 8 hr for 6 doses was given to adult Lewis x Brown Norway rats. This resulted in death of the proliferating crypt cells, followed by regeneration of the mucosa from the surviving crypt cells, with recovery by Day 8. This mucosal damage and recovery was reflected by histological changes and a decrease in activity of mucosal disaccharidases and alkaline phosphatase. Both mucosal and plasma DAO levels also fell markedly to less than 10% of basal levels (N = 30, p less than 0.005) by Day 4 and recovered with a time course similar to the histological and biochemical changes indicative of injury and recovery. With increasing dosage and/or increasing duration of ara-C treatment, mucosal injury was progressive, with increasing loss of both plasma and mucosal DAO levels as compared to controls (N = 38, p less than 0.005). Plasma DAO levels in three patients with leukemia following ara-C chemotherapy decreased markedly to less than 30% of basal pretreatment levels (p less than 0.05) by Days 9 to 12, with a time course that was compatible with clinical intestinal mucosal injury. Our data document that plasma DAO levels reflect the mucosal injury and subsequent recovery after ara-C treatment in the rat and humans. Thus, plasma DAO may serve as a marker of the integrity of the intestinal mucosa after chemotherapy.