Journal
BIOCHEMICAL PHARMACOLOGY
Volume 59, Issue 8, Pages 993-996Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0006-2952(99)00405-0
Keywords
cytochrome P450 reductase; indolequinone bioreductive drugs; EO9; transfected P450R
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Funding
- Medical Research Council [G0500366] Funding Source: Medline
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Analogues of EO9 (3-hydroxymethyl-5 -aziridinyl-1 -methyl-2[1H -indole-4-7-dione]prop-2-en-1-1-ol) which lack functionality at either the C-2 or C-3 position were synthesised. The aim was to establish the importance of each group towards toxicity and to give an indication as to whether substitution at either posit-ion altered activation and toxicity after metabolism by cellular NADPH: cytochrome c (P450) reductase (P450R). MDA231 breast cancer cells were transfected with the cDNA for human P450R and stable clones were isolated. These high P450R-expressing clones were used to determine the aerobic and hypoxic toxicity of EO9 and the two analogues that lacked functionality at either C-2 or C-3. The results showed that P450R was strongly implicated in the bioactivation of EO9 and its analogues under both of these conditions. This data also showed that the C-3 functionality was primarily implicated in hypoxic toxicity. (C) 2000 Elsevier Science Inc.
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