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-metab olizing enzymes and the immunochemical detection of P4501A and 2B hale been investigated in liver microsomes and cytosol of male rats fed fo r 15 days with diets containing canthaxanthin, astaxanthin, lycopene o r lutein (as lutein eaters) (300 mg/kg diet) and in rats fed increasin g levels (10, 30, 100 and 300 ppm) of canthasanthin or astaxanthin in the diet. 2. Canthaxanthin increased the liver content of P450, the ac tivities of NADH- and NADPH-cytochrome c reductase, and produced a sub stantial increase of some P450-dependent activities, especially ethoxy resorufin O-deethylase (EROD) (x 139) and methoxyresorufin O-demethyla se (MROD) (x 26). Canthaxanthin also increased pentoxy-(PROD) and benz oxyresorufin O-dealkylases (BROD), but did nor affect NADPH-cytochrome c reductase and erythromycin N-demethylase (ERDM) activities and decr eased nitrosodimethylamine N-demethylase (NDMAD) activity. Phase II p- nitro-phenol UDP-glucuronosyl transferase (4NP UGT) and quinone reduct ase (QR) activities were also increased by canthaxanthin treatment. Th ese enhancing effects on EROD, MROD and 4NP-UGT were clearly detectabl e at a dose as low as 10 ppm of canthaxanthin in the diet; the inducti on of QR was only observed in rats fed greater than or equal to 100 pp m. Astaxanthin induced the same pattern of enzymes activities as canth axanthin, but to a lesser extent: its effects on phase I enzymes and 4 NP-UGT were observed in rats fed greater than or equal to 100 ppm, and QR was not increased. Western blots of microsomal proteins clearly sh owed the induction of P4501A1 and 1A2 by canthaxanthin and astaxanthin . By contrast, lutein had no effect on the phase I and II xenobiotic-m etabolizing 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 coin duce 4NP-UGT and QR, just like polycyclic aromatic hydrocarbon, beta-n aphtoflavone or dioxin (TCDD). However, these latter classical P4501A inducers also induce aldehyde dehydrogenase class 3 (ALDH3); this enzm e is not increased, or only marginally, by canthaxanthin and astaxanth in. These two oxocarotenoids form a new class of inducers of P4501A, a re structurally very different from the classical inducers quoted abov e, which are ligands of the AH receptor.