The carotenoid lycopene differentially regulates phase I and II enzymes in dimethylbenz[a]anthracene-induced MCF-7 cells.
OBJECTIVE
Lycopene is a carotenoid widely distributed in fruit and vegetables. Epidemiological studies suggest that lycopene consumption is associated with decreased cancer risk. Animal studies have revealed that lycopene may protect against dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis in the breast. Polycylic aromatic hydrocarbons (PAH) are environmental toxicants that can be metabolized by two phase I enzymes, cytochrome P450 1A1 and 1B1. Products formed by these reactions are DNA-attacking moieties. Mutation generated by these genotoxic intermediates is believed to be an important step in cancer initiation. Some phase II detoxifying enzymes, such as uridine diphosphate (UDP)-glucuronosyltransferases (UGT), facilitate the elimination of these genotoxic moieties. In the present study, the mechanism by which lycopene prevented PAH-induced carcinogenesis in the breast was investigated in a cell culture model MCF-7.


METHODS
The inhibitory action of lycopene on CYP1 enzymes was assessed in recombinant protein and cell culture using ethoxyresorufin-O-deethylase assay. Messenger RNA expressions of CYP1A1 and 1B1, and UGT were estimated by semi-quantitative reverse transcription-polymerase chain reaction. Cells were co-treated with tritiated DMBA and lycopene for quantifying the protection of the phytocompound against DNA lesion generated from the DMBA metabolites.


RESULTS
Lycopene inhibited recombinant CYP1A1 and CYP1B1 with estimated K(i)s in the micromolar range. In MCF-7 cells, lycopene administration slightly reduced the DMBA-induced ethoxyresorufin-O-deethylase activity by 20%. Meanwhile, a four-fold increase in microsomal UGT activity was observed.


CONCLUSIONS
The present study illustrated that phase I enzyme inhibition and phase II enzyme induction were the underlying chemoprotective mechanisms of lycopene against PAH-induced toxicity.
Wang
Huan
H
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Leung
Lai K
LK
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000032:analysis; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001943:Breast Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D002273:Carcinogens / Q000032:analysis; D002338:Carotenoids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D000077276:Lycopene; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D002338:Carotenoids; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D014453:Glucuronosyltransferase; D000077276:Lycopene