Effects of canthaxanthin, astaxanthin, lycopene and lutein on liver xenobiotic-metabolizing enzymes in the rat

Abstract

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.

AH receptor agonist activity in human blood measured with a cell-based bioassay: Evidence for naturally occurring AH receptor ligands in vivo

“…Commencement of a high-vegetable diet, which would not be expected to increase the consumption of PCDD/Fs and PCBs, in this study caused significant increases in the blood IEQ. Numerous studies have reported that common dietary phytochemicals such as flavanoids, indoles, polyphenolics, and oxidized carotenoids possess AHR agonist activity (Gradelet et al, 1996;Heath-Pagliuso et al, 1998;Denison and Nagy, 2003;Jeuken et al, 2003;Zhang et al, 2003). Many of these natural AHR agonists have been measured in human blood in the low micromolar range (Nakagawa et al, 1997;Paganga and Rice-Evans, 1997;de Vries et al, 1998).…”

All-trans retinoic acid inhibits the recruitment of ARNT to DNA, resulting in the decrease of CYP1A1 mRNA expression in HepG2 cells

“…Previous reports have proposed reliable evidence that tryptophan and its metabolites could act as endogenous agonists at the AHR and induce AHR-regulated gene transcription both in vivo and in cultured cells [10,11]. In addition, there is evidence of a ligand-independent pathway that a variety of agents can transcriptionally activate CYP1A1, as measured by the AHR response, including hormones, omeprazole, and notably carotenoids, even though they lack the chemical characteristics typically associated with high AHR affinity [12][13][14][15][16][17][18]. However, there is no definitive explanation for the physiological function of AHR in the various tissues in which it is expressed, particularly when addressing the question of which endogenous compounds regulate AHR at physiological concentrations, the exception being tryptophan.…”

Opinion of the Scientific Panel on Dietetic products, nutrition and allergies [NDA] related to an application on the use of a-tocopherol-containing oil suspension of lycopene from Blakeslea trispora as a novel food ingredient

“…Such a change in BaP metabolism upon pre-or co-treatment with lycopene may result for example from an effect of lycopene on biotransformation enzymes. Lycopene intake was reported to induce ethoxyresorufin O-dealkylase and benzyloxyresorufin O-dealkylase activities in the liver (Breinholt et al, 2000) and to decrease benzyloxyresorufin O-dealkylase activity in the lungs (Jewell and O'Brien, 1999) and nitrosodimethylamine N-demethylase activity in the liver (Gradelet et al, 1996).…”

“…• Gradelet et al (1996) studied the effect of various carotenoids including lycopene (5% lycopene oleoresin from tomato) on several biotransformation enzymes in the liver of male rats fed for 15 days diets containing 300 mg lycopene/ kg diet, leading to an intake of approximately 15 mg/kg body weight/day. Lycopene was reported not to induce any of the parameters measured including liver P450 content, ethoxyresorufin O-dealkylation, methoxyresorufin O-dealkylation, benzyloxyresorufin O-dealkylation, and erythromycin N-demethylation activity.…”

“…• rats at concentrations of 0 (control) and 300 mg lycopene oleoresin from tomato/kg diet, corresponding to approximately 15 mg/kg body weight/day, for 15 days (Gradelet et al, 1996), in a study on the effects of various carotenoids on liver xenobioticmetabolizing enzymes;…”