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• W2109011132 endingPage "118" @default.
• W2109011132 startingPage "101" @default.
• W2109011132 abstract "This study investigated the effect of inducers on the major enzymes responsible for metabolising the quinone antitumour agent mitoxantrone, and on its cytotoxicity in MCF 7 human breast cancer cells. Four inducers were used: 1,2-benzanthracene (BA); phenobarbitone (PB); rifampicin (R) and dexamethasone (DEX). Of these, BA was the most effective, increasing cytochrome P450 dependent metabolism 64-fold and DT-diaphorase activity 1.6-fold. R did not cause an increase in any of the enzyme activities measured and, in fact, inhibited glutathione peroxidase activity. PB and DEX increased NADPH cytochrome c reductase activity but had no effect on either DT-diaphorase or cytochrome P450 dependent activities. BA potentiated the cytotoxicity of mitoxantrone in terms of leakage of lactate dehydrogenase (LDH) activity and loss of reduced glutathione (GSH) and protein from cultures. PB had a smaller potentiating effect on cytotoxicity and DEX had no effect. Studies with the enzyme inhibitors, dicoumarol (inhibits DT-diaphorase) and metyrapone (inhibits cytochrome P450), indicate that at least two reactive species are involved in mitoxantrone cytotoxicity. One intermediate, formed by cytochrome P450, caused LDH leakage and GSH depletion. Formation of the second intermediate was catalysed by DT-diaphorase and this hydroquinone caused loss of intracellular protein and GSH. We propose that autooxidation of the hydroquinone resulting in generation of reactive oxygen species contributes to mitoxantrone cytotoxicity. Concomitant exposure to inducing agents may alter the cytotoxicity associated with many cytotoxic drugs, not just mitoxantrone, and this is an important consideration as many cytotoxics have a narrow therapeutic index." @default.
• W2109011132 created "2016-06-24" @default.
• W2109011132 creator A5044068686 @default.
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• W2109011132 date "1995-07-01" @default.
• W2109011132 modified "2023-09-27" @default.
• W2109011132 title "The activity of xenobiotic enzymes and the cytotoxicity of mitoxantrone in MCF 7 human breast cancer cells treated with inducing agents" @default.
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• W2109011132 doi "https://doi.org/10.1016/0009-2797(94)03603-6" @default.
• W2109011132 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/7541730" @default.
• W2109011132 hasPublicationYear "1995" @default.
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