Persistent correction of hyperglycemia in streptozotocin-nicotinamide-induced diabetic mice by a non-conventional radical scavenger.

We previously reported that in a diabetes mouse model, characterised by moderate hyperglycaemia and reduced beta-cell mass, the radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate di-hydrochloride (IAC), a non-conventional cyclic hydroxylamine derivative, improves metabolic alterations by counteracting beta-cell dysfunction associated with oxidative stress. The aims of this study were to ascertain whether the beneficial effects of IAC treatment could be maintained after its discontinuation and further elucidate the underlying mechanisms. Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Diabetic mice were treated for 7 weeks with various doses of IAC (7.5, 15, or 30 mg/kg b.w./die i.p.) and monitored for additional 8 weeks after suspension of IAC. Then, pancreatic tissue was used for determination of beta-cell mass by immunohistochemistry and beta-cell ultrastructural analysis. STZ-NA mice showed moderate hyperglycaemia, glucose intolerance and reduced beta-cell mass (25% of controls). IAC-treated STZ-NA mice (at both doses of 15 and 30 mg/kg b.w.) showed long-term reduction of hyperglycaemia even after discontinuation of treatment, attenuation of glucose intolerance and partial preservation of beta-cell mass. The lowest IAC dose was much less effective. Plasma nitrotyrosine levels (an oxidative stress index) significantly increased in untreated diabetic mice and were lowered upon IAC treatment. At ultrastructural level, beta cells of IAC-treated diabetic mice were protected against degranulation and mitochondrial alterations. In the STZ-NA diabetic mouse model, the radical scavenger IAC induces a prolonged reduction of hyperglycaemia associated with partial restoration of beta-cell mass and function, likely dependent on blockade of oxidative stress-induced damaging mechanisms.

Alteration of xenobiotic metabolizing enzymes by resveratrol in liver and lung of CD1 mice.

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.

Perturbation of rat hepatic metabolising enzymes by folic acid supplementation.

An adequate folate intake minimizes the risk of various cancers and other disorders such as vascular diseases and neural tube defects. However, meta-analyses revealed difficulties in supporting the relationship between folate intake and the risk of cancer. Interestingly, there have been no reports to date on the potential ability of folate to modulate xenobiotic metabolising enzymes (XMEs), the inhibition of bioactivating Phase-I XMEs and/or induction of detoxifying Phase-II XMEs being one of the most evoked cancer chemopreventive strategies. Here, several CYP-dependent oxidations were studied in liver sub-cellular preparations from Sprague-Dawley rats receiving rodent chow supplemented with folic acid daily, for 1 or 2 consecutive months. Using either specific substrates as probes of different CYP isoforms or the regio- and stereo-selective metabolism of testosterone as a multibiomarker, we found that folic acid markedly inactivated most of the Phase-I XME analysed; up to 54% for the CYP1A1-linked deethylation of ethoxyresorufin in males, and up to 86% for the testosterone 2alpha-hydroxylase (CYP2C11) in females, after 2 months treatment. The Phase-II marker glutathione S-transferase significantly increased (~107%) after 1 month of supplementation in females only. These changes, if reproduced in humans might have public health implications. These data suggest caution in performing folate chemoprevention trials before its overall toxicological characterization has been fully addressed.