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Conflicting data on the anticancer properties of the polyphenolic natural product resveratrol (RSV) have been reported. Since the inhibition of "bioactivating" Phase-I xenobiotic metabolizing enzymes (XMEs) and/or induction of "detoxifying" Phase-II XMEs have long been considered important cancer chemopreventive strategies, in the current study we investigated the effect of RSV treatment on several Cytochrome P450 (CYP)-dependent oxidations and Phase-II markers in liver and lung subcellular preparations from CD1 male mice. These mice were i.p treated with RSV (25 or 50mg/Kg b.w.) daily for one or for seven consecutive days. Using either specific probes for different CYPs, or the regio- and stereo-selective metabolism of testosterone, we found that most of the Phase-I XMEs were significantly suppressed (up to approximately 61% loss for the CYP3A1/2-linked 6 beta-hydroxylation of testosterone in liver and up to approximately 97% loss for 2 alpha-hydroxylase in lung) following RSV treatment for 7 days at 50mg/kg b.w. Glutathione S-transferase was significantly inhibited, particularly in lung (approximately 76% loss of activity) after single administration of 25mg/kg b.w. A different response for the UDP-glucuronosyl transferase was observed, where a significant induction was seen (approximately 83%) in the liver and a significant reduction was observed in the lung (up to approximately 83% loss) following treatment with 25mg/kg b.w. for seven days. These data indicate that murine XMEs are altered by RSV, and that this alteration is dependent on the RSV dose, duration and way of administration. These results could provide mechanistic explanations for the conflicting chemopreventive results reported for RSV.

it was previously found that fenarimol, vinclozolin or acephate, three of the most used pesticides worldwide, provoked a marked perturbation of murine cytochrome P450 (CYP)-linked monooxygenases. Here, to more closely mimic human exposure, it was investigated whether different pesticide combinations administered i.p. in male Swiss Albino CD1 mice in single or repeated fashion (daily, for three consecutive days), affect CYP-dependent oxidations. The four simulated mixtures showed a complex pattern of CYP induction and suppression, especially after repeated injection. For example, while fenarimol alone was the most inducing agent - reaching a 79-fold increase over control in testosterone 2 alpha-hydroxylase - followed by vinclozolin and acephate, coadministration with the former markedly reduced induction. Coadministration with vinclozolin, determined various positive and negative modulations. An increase of CYP2B1/2 and CYP3A1/2-associated oxidases and a decrease of ethoxycoumarin metabolism was observed in the acephate and vinclozolin mixture. An equivalent or reduced CYP expression, if compared to double combinations, was seen using the complete mixture. Taken as a whole, the unpredictability of the recorded effects with simple mixtures, shrinks the misleading extrapolation performed on a single pesticide. If reproduced in human, such changes, altering either endogenous metabolism or biotransformation of ubiquitous toxins, might have public health implications. (c) 2007 Elsevier Ltd. All rights reserved.

This work aimed to investigate whether the insecticide acephate (125 or 250 mg/kg b.w.) or diflubenzuron (752 or 1075 mg/kg b.w.), two of the most widely used pesticides worldwide, impairs CYP-linked murine metabolism in liver, kidney and lung microsomes after repeated (daily, for three consecutive days) i.p. administration. The regio- and stereo-selective hydroxylation of testosterone was used as multibiomarker of different CYP isoforms. Both gender and tissue specific effects were observed. Lung was the most responsive tissue to induction by lower diflubenzuron dose, as exemplified by the marked increase of testosterone 7alpha-hydroxylation (CYP2A) (up to 13-fold) in males. Higher dose produced a generalized inactivation. At the lower dose acephate induced 6beta- (CYP3A1/2, liver) as well as 2beta- (CYP2B1/2, kidney) hydroxylase activities ( approximately 5 and approximately 4-fold increase, respectively) in males. In females, a marked suppression of the various hydroxylations was observed. At 250 mg/kg of acephate, animals did not survive. Induction of the most affected isoforms was sustained by immunoblotting analysis. Corresponding human CYP modulations might disrupt normal physiological functions related to these enzymes. Furthermore, the co-mutagenic and promoting potential of these pesticides, phenomena linked to CYP upregulation (e.g. increased bioactivation of ubiquitous pollutants and generation of oxygen free radicals) are of concern for a more complete definition of their overall toxicological potential.