Journal Article

Induction of cytochrome P450 enzymes and over-generation of oxygen radicals in beta-carotene supplemented rats

Moreno Paolini, Alessandra Antelli, Laura Pozzetti, Denisa Spetlova, Paolo Perocco, Luca Valgimigli, Gian Franco Pedulli and Giorgio Cantelli-Forti

in Carcinogenesis

Volume 22, issue 9, pages 1483-1495
Published in print September 2001 | ISSN: 0143-3334
Published online September 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.9.1483
Induction of cytochrome P450 enzymes and over-generation of oxygen radicals in beta-carotene supplemented rats

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Effects of beta-carotene (βCT) on microsomal CYP-linked monooxygenases were investigated using both the regio- and stereo-selective hydroxylation of testosterone (as multibiomarker) and highly specific substrates as probes of various isoenzymes. CYP-catalyzed reactions were studied in the liver, kidney, lung and intestine of Sprague–Dawley rats of both sexes supplemented with 250 or 500 mg/kg body wt βCT (per os) in a single or repeated (daily for 5 days) fashion. Generalized boosting effects (2–15-fold increases) were observed in the various tissues for carcinogen metabolizing enzymes associated with CYP1A1/2, CYP3A1/2, CYP2E1, CYP2B1/2 and CYP2C11. Induction of the most affected CYPs was corroborated by western blot linked to densitometric analyses. Measurement of reactive oxygen species (ROS) produced by subcellular preparations from either control or βCT supplemented rats was performed by EPR detection of the nitroxide radical yielded by the reaction with ROS of the hydroxylamine spin probe bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate. Marked ROS over-generation associated with CYP induction (up to 33-fold increase in the liver) was recorded in the various organs (liver > lung > intestine > kidney). CYP and ROS induction are substantially in keeping with the concentration of βCT accumulated in the various tissues, the liver being the most affected organ. These findings are consistent with the concept that βCT is a pro-oxidant and potentially co-carcinogenic pro-vitamin, and may help explain why, in large quantities, it can have harmful effects in humans.

Keywords: APND, aminopyrine N-demethylase; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; βCT, beta-carotene; CARET, Carotene and Retinol Efficacy Trial; CYP, cytochrome P450; ECOD, ethoxycoumarin O-deethylase; EPR, electronic paramagnetic resonance; EROD, ethoxyresorufin O-deethylase; MROD, methoxyresorufin O-demethylase; OPP, oxygen partial pressure; pNFH, p-nitrophenol hydroxylase; PROD, pentoxyresorufin O-dealkylase; RAR, retinoic acid receptor; ROH, retinol; ROS, reactive oxygen species; TH, testosterone hydroxylase.

Journal Article.  10994 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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