EVIDENCE OF TOXIC METABOLITE STRESS IN BLACK SOUTH-AFRICANS WITH CHRONIC-PANCREATITIS

We report the results of a further study to test our hypothesis that t oxic metabolite stress is germane to heightened free radical activity and hence to the genesis of chronic pancreatitis. Consecutive black So uth African patients with clinically quiescent chronic pancreatitis we re studied, provided that the diagnosis had been made within the previ ous 2 years and that they did not have overt liver disease. All of the m had been advised to stop drinking alcohol. Analysis of an early morn ing sample of urine showed a lower ratio of inorganic to ester sulphat e (P < 0.001) and a higher ratio of D-glucaric acid to creatinine (P < 0.02) in the group of 14 patients than in 15 local controls, while pl asma analysis showed a lower concentration of glutathione (GSH) in the patients (P < 0.001). This evidence of increased utilisation of phase II conjugative pathways of xenobiotic disposal was in keeping with on -going toxic metabolite stress from heightened phase I oxidative metab olism in the group of patients. Parallel studies of theophylline pharm acokinetics showed heightened drug clearance compatible with induced c ytochrome P-4501A2 in two patients, whereas increased activity of gamm a-glutamyl transferase in serum suggested persisting induction of P-45 02E1, as by ethanol, in several others. The contemporaneous increases in free radical activity and utilisation of xenobiotic disposal pathwa ys in Sowetan Africans with chronic pancreatitis is in line with the t oxic metabolite concept of disease pathogenesis.