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Title: Natural substrates and inhibitors of CYP1 family enzymes
Author: Androutsopoulos, Vasilis
ISNI:       0000 0004 2670 6933
Awarding Body: De Montfort University
Current Institution: De Montfort University
Date of Award: 2009
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The enzymes CYP 1A1 and CYP 1B1 have been shown to be overexpresscd in a wide variety of tumors. The enzyme CYP1B1 has been shown to convert a cancer preventative agent (resveratrol) to a compound with antileukemic activity (picccatannol). Based on these findings interactions of CYP1 family enzymes with cancer preventative flavonoids, that have structure similar to resveratrol, were investigated. The flavonols quercetin, myricetin and kaempferol and the flavones chrysin, eupatorin and diosmetin inhibit the dealkylation of 7-ethoxyresorufin to resorufin by CYP1B1, and to a lesser extent by CYP1A1 (with the exception of chrysin) and CYP1A2. The flavones diosmetin, eupatorin, sinensetin, genkwanin, scutellarein and chrysin are substrates for CYP1 family enzymes. Furthermore the metabolism of natural flavones and their cytotoxic action in MDA-MB 468, MCF7 human breast adenocarcinoma and MCF l0A human breast cells, as well as the ability to inhibit the progression of these cells through the phases of the cell cycle was evaluated. The flavones diosmetin, genkwanin and eupatorin were shown to be metabolised in MDA-MB 468 cells and MCF7 cells pretreated with 10nM TCDD for 24 hrs but not in MCF10A cells or MCF7 cells with no TCDD treatment. The latter compounds along with other structurally related flavones, were shown to inhibit the growth of MDA-MB 468 and MCF7 cells, while having minor effects on the growth of MCF10A cells (with the exception of baicalein). The flavones eupatorin and cirsiliol caused G₂/M arrests in MDA-MB 468 cells at 48 hr and diosmetin and sinensetin caused G₁ arrests in the same time period. Finally the ability of natural flavones to induce the expression of CYP1 family enzymes in MCF7 cells was investigated. The flavones diosmetin, genkwanin, eupatorin eupatorin-5-methyl ether and cirsiliol induced CYP1 enzyme expression in MCF7 cells after 24 hr treatment, as evident by increased EROD activity. Eupatorin and cirsiliol caused an increase in CYP1B1 and CYP1A1 mRNA levels, as shown by RTPCR. Overall the data confirm the hypothesis that CYP1B1 and CYP1A1 can act as tumour suppressor enzymes, via metabolic activation of naturally occuring flavonoids. Thus the results provide a novel model on the mechanism by which selected flavonoids exert their chemopreventative action.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available