Effects of canthaxanthin, astaxanthin, lycopene and lutein on liver xenobiotic-metabolizing enzymes in the rat.
1. The catalytic activities of several phase I and II xenobiotic-metabolizing enzymes and the immunochemical detection of P4501A and 2B have been investigated in liver microsomes and cytosol of male rats fed for 15 days with diets containing canthaxanthin, astaxanthin, lycopene or lutein (as lutein esters) (300 mg/kg diet) and in rats fed increasing levels (10, 30, 100 and 300 ppm) of canthaxanthin or astaxanthin in the diet. 2. Canthaxanthin increased the liver content of P450, the activities of NADH- and NADPH-cytochrome c reductase, and produced a substantial increase of some P450-dependent activities, especially ethoxyresorufin O-deethylase (EROD) (x 139) and methoxyresorufin O-demethylase (MROD) (x 26). Canthaxanthin also increased pentoxy-(PROD) and benzoxyresorufin O-dealkylases (BROD), but did not affect. NADPH-cytochrome c reductase and erythromycin N-demethylase (ERDM) activities and decreased nitrosodimethylamine N-demethylase (NDMAD) activity. Phase II p-nitrophenol UDP-glucuronosyl transferase (4NP-UGT) and quinone reductase (QR) activities were also increased by canthaxanthin treatment. These enhancing effects on EROD, MROD and 4NP-UGT were clearly detectable at a dose as low as 10 ppm of canthaxanthin in the diet; the induction of QR was only observed in rats fed > or = 100 ppm. Astaxanthin induced the same pattern of enzymes activities as canthaxanthin, but to a lesser extent: its effects on phase I enzymes and 4NP-UGT were observed in rats fed > or = 100 ppm, and QR was not increased. Western blots of microsomal proteins clearly showed the induction of P4501A1 and 1A2 by canthaxanthin and astaxanthin. By contrast, lutein had no effect on the phase I and II xenobiotic-metabolizing enzymes activities measured. Lycopene only decreased NDMAD activity. 3. The two 4-oxocarotenoids canthaxanthin and astaxanthin are substantial inducers of liver P4501A1 and 1A2 in the rat, and coinduce 4NP-UGT and QR, just like polycyclic aromatic hydrocarbon, beta-naphtoflavone or dioxin (TCDD). However, these latter classical P4501A inducers also induce aldehyde dehydrogenase class 3 (ALDH3); this enzyme is not increased, or only marginally, by canthaxanthin and astaxanthin. These two oxocarotenoids form a new class of inducers of P4501A, are structurally very different from the classical inducers quoted above, which are ligands of the AH receptor.
Gradelet
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S
Unité de Toxicologie Nutritionnelle, Institut National de la Recherche Agronomique, DIJON, France.
Astorg
P
P
Leclerc
J
J
Chevalier
J
J
Vernevaut
M F
MF
Siess
M H
MH
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002338:Carotenoids / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004032:Diet; D004435:Eating / Q000187:drug effects; D015151:Immunoblotting; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014801:Vitamin A / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
D007527:Isoenzymes; D015262:Xenobiotics; D014801:Vitamin A; D002338:Carotenoids; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases