N-HYDROXYLATION OF DAPSONE BY MULTIPLE ENZYMES OF CYTOCHROME-P450 - IMPLICATIONS FOR INHIBITION OF HAEMOTOXICITY

1 The adverse reactions associated with the administration of dapsone are believed to be caused by metabolism to its hydroxylamine. Previous reports suggest that CYP3A4 is responsible for this biotransformation [1]. 2 Data presented in this paper illustrate the involvement of mor e than one cytochrome P450 enzyme in dapsone hydroxylamine formation u sing human liver microsomes. Eadie-Hofstee plots demonstrated bi-phasi c kinetics in several livers. No correlation could be established betw een hydroxylamine formation and CYP3A concentrations in six human live rs (r = -0.47; P = 0.34). 3 Studies with low molecular weight inhibito rs illustrate the importance of CYP2C9 and CYP3A in dapsone N-hydroxyl ation. 4 Differential sensitivity of dapsone N-hydroxylation to select ive CYP inhibitors indicated that the contribution of individual CYP e nzymes varies between livers. Selective inhibition ranged from 6.8 to 44.4% by 5 mu M ketoconazole, and from 24.0 to 68.4% by 100 mu M sulph aphenazole. The extent of inhibition, by either ketoconazole or sulpha phenazole was dependent on the CYP3A content of the liver. 5 The level s of expression of these cytochrome P450 enzymes may be an important d eterminant of individual susceptibility to the toxic effects of dapson e, and may influence the ability of an enzyme inhibitor to block dapso ne toxicity in vivo. Because of the inability to produce complete inhi bition, selective CYP inhibitors are unlikely to offer any clinical ad vantage over cimetidine in decreasing dapsone hydroxylamine formation in vivo.