Dose-response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat.
The administration of lycopene to female rats at doses ranging from 0.001 to 0.1 g/kg b.w. per day for 2 weeks was found to alter the drug-metabolizing capacity and antioxidant status of the exposed animals. An investigation of four cytochrome P450-dependent enzymes revealed that benzyloxyresorufin O-dealkylase activity in the liver was significantly induced in a dose-dependent fashion at all lycopene doses investigated. Likewise, ethoxyresorufin O-dealkylase activity was induced, although only at the two highest lycopene concentrations tested. An investigation of selected phase 2 detoxification enzymes provided evidence that lycopene was capable of inducing hepatic quinone reductase, approximately two-fold, at doses between 0.001 and 0.05 g/kg b.w. per day, whereas no effect was observed at the remaining doses tested. Glutathione transferase, using the two substrates, 2,4-dichloronitrobenzene and 1-chloro-2, 4-dinitrobenzene, was significantly induced at the 0.1 g/kg b.w. per day dose, whereas no effect was observed at the remaining lycopene doses. Analysis of the antioxidant status of the blood compartment revealed that three out of four antioxidant enzymes were affected by lycopene treatment. The activity of superoxide dismutase was thus significantly induced at lycopene doses of 0.005 and 0.05 g/kg b.w, whereas glutathione reductase and glutathione peroxidase was only induced at the 0.005 g/kg b.w. per day dose. For all antioxidant enzymes investigated, the activities seemed to return to the control level after exerting peak induction at doses between 0.005 and 0.05 g/kg b.w. per day. The explanation for this remains unknown. The plasma concentration of lycopene at dietary levels of 0.001, 0.005, 0.05 and 0.1 g/kg b.w. per day was estimated to be 16, 32, 71 and 67 nM, which is barely within the lower range of the mean human plasma concentration of lycopene, which ranges from 70-1790 nM. Oxidative stress induced by the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), and investigated by analyzing for malondialdehyde in plasma, was not found to be affected by prior lycopene exposure. The level of PhIP-DNA adducts in the liver or colon was likewise not affected by lycopene at any dose. Overall, the present study provides evidence that lycopene administered in the diet of young female rats exerts minor modifying effects toward antioxidant and drug-metabolizing enzymes involved in the protection against oxidative stress and cancer. The fact that these enzymatic activities are induced at all of these very low plasma levels, could be taken to suggest that modulation of antioxidant and drug-metabolizing enzymes may indeed be relevant to humans, which in general exhibit a plasma lycopene level several fold above the effective levels observed in this study.
Breinholt
V
V
Institute of Food Safety and Toxicology, Division of Biochemical and Molecular Toxicology, Danish Veterinary and Food Administration, Morkhoj Bygade 19, 2860, Soborg, Denmark. vib@fdir.dk
Lauridsen
S T
ST
Daneshvar
B
B
Jakobsen
J
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002338:Carotenoids / Q000097:blood / Q000494:pharmacology*; D003106:Colon / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D018736:DNA Adducts / Q000378:metabolism; D004137:Dinitrochlorobenzene / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D000077276:Lycopene; D008861:Microsomes / Q000201:enzymology; D009153:Mutagens / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009578:Nitrobenzenes / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000975:Antioxidants; D018736:DNA Adducts; D004137:Dinitrochlorobenzene; D007093:Imidazoles; D009153:Mutagens; D009578:Nitrobenzenes; D002338:Carotenoids; C053747:2,4-dichloro-1-nitrobenzene; D003577:Cytochrome P-450 Enzyme System; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase; D000077276:Lycopene