Ah receptor-dependent CYP1A induction by two carotenoids, canthaxanthin and beta-apo-8'-carotenal, with no affinity for the TCDD binding site.
The assays of several phase I and phase II xenobiotic-metabolizing enzyme activities, as well as CYP1A immunoblot analysis, were performed in liver microsomes and cytosol of male C57BL/6 mice (Ah receptor-responsive), of male DBA/2 mice (Ah receptor-low responsive) and of female Ah receptor gene knockout mice that were fed diets containing 300 mg/kg of a nonprovitamin A carotenoid, canthaxanthin, or a provitamin A carotenoid, beta-apo-8'-carotenal for 14 days, or which were injected i.p. with 3-methylcholanthrene. Previous studies have shown that some carotenoids, such as canthaxanthin and beta-apo-8'-carotenal, are strong inducers of liver CYP1A1 and 1A2 when given to rats. In this work, only canthaxanthin induced both CYP1A1 and 1A2 in C57BL/6 mice, whereas beta-apo-8'-carotenal induced only CYP1A2 in this strain. Neither of the two carotenoids modified CYP1A1/2 protein contents or enzyme activities in Ah receptor-low responsive DBA/2 or in Ah receptor gene knockout mice. Cytosol prepared from C57BL/6 mice liver tissue was incubated with [3H] 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the presence of canthaxanthin or beta-apo-8'-carotenal and analyzed by sucrose density gradient sedimentation: neither of the carotenoids, even when present in large excess, competed with TCDD for the TCDD binding site of the cytosolic Ah receptor of C57BL/6 mice. In brief, the carotenoids canthaxanthin or beta-apo-8'-carotenal induced Cyp1a genes in mice through an Ah receptor-dependent pathway, but did not bind to the Ah receptor.
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Unite de Toxicologie Nutritionnelle, INRA, BV 1540, Dijon, France.
Astorg
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P
Pineau
T
T
Canivenc
M C
MC
Siess
M H
MH
Leclerc
J
J
Lesca
P
P
D000818:Animals; D001665:Binding Sites; D016644:Canthaxanthin / Q000008:administration & dosage / Q000494:pharmacology*; D002338:Carotenoids / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000502:physiology*
D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D002338:Carotenoids; D016644:Canthaxanthin; D003577:Cytochrome P-450 Enzyme System; C004984:apocarotenal