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This study has identified a mechanism of satraplatin activation involving metal-containing redox proteins and the transfer of electrons to the Pt(IV) drug from protein-complexed metal ions. Heme proteins may act by this mechanism as reducing agents for the activation of satraplatin in vivo.

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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 more than one cytochrome P450 enzyme in dapsone hydroxylamine formation using human liver microsomes. Eadie-Hofstee plots demonstrated bi-phasic kinetics in several livers. No correlation could be established between hydroxylamine formation and CYP3A concentrations in six human livers (r = -0.47; P = 0.34). 3 Studies with low molecular weight inhibitors illustrate the importance of CYP2C9 and CYP3A in dapsone N-hydroxylation. 4 cytosis, fever and rashes, occurs in a small proportion of the population (< 1: 2000) [ 14,15]. Stevens-Johnson syndrome has also been reported in patients on dapsone therapy [ 16]. The haemotoxicity of dapsone is mediated by the hydroxylamine metabolite, which is capable of being co-oxidized with haemoglobin (Hb) in the red blood cell to produce nitroso dapsone ( Figure 1) and methaemoglobin (Met-Hb) [9,10]. The nitroso compound can then be reduced back to the hydroxylamine by the action of glutathione, so that a futile oxidationreduction cycle exists in which the cell uses oxygen to deplete glutathione and NADPH [17]. Dapsoneinduced toxicity to white cells is poorly understood, but is also thought to be a consequence of hydroxylamine UDPGA Human liver samplesSamples were from histologically normal livers which had been removed and transferred to the laboratory within 30 min of death. The liver was sliced into 10-20 g portions, placed in vials and frozen in liquid nitrogen. These samples were stored at -80°C until the preparation of microsomes. Ethical approval was granted and consent was obtained from the donors' relatives before removal of the liver. Preparation ofmicrosomesThe frozen liver was thawed and minced in ice cold 0.067 M phosphate buffer (pH 7.5) containing 1.15% KCI (w/v). The livers were then homogenized using a motor driven Polytron homogenizer. The homogenates were centrifuged at 10 000 g for 20 min at 40 C to remove mitochondria, nuclei and cell debris. The supernatants were decanted off and centrifuged at 105 000 g for 60 min at 4°C to produce the microsomal pellet. lated using a Spectra-Physics Chromjet Integrator. An internal standard was not necessary due to a good correlation between radiometric and u.v. analysis of hydroxylamine formation (r=0.988). LC-MS analysis was performed using a j-Bondapak 10 C18 column (30 cm x 3.9 mm). Samples were eluted with a mobile phase consisting of ammonium formate (6 mm, pH 3.5) and acetonitrile (80:20 v/v) at a flow rate of 1 ml min-'. The mobile phase was delivered by two Jasco PU980 pumps (Jasco Corporation, Tokyo, Japan hydroxylamine (inhibition= 23.3 % at 5 giM ketoconazole, and 48.7% at 100 gIM sulphaphenazole), indicating a role for CYP3A and CYP2C9.In order to investigate inhibition further, the experiments with ketoconazole and sulphaphenazole wer...

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