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.
Department of Pharmacology, Molecular Toxicology Unit, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. labpaolini.farmacologia@unibo.it
D
D
Canistro
L
L
Pozzetti
A
A
Sapone
M
M
Broccoli
B
B
Bonamassa
V
V
Longo
V
V
Lubrano
J
J
Barillari
G L
GL
Biagi
M
M
Paolini
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000633:toxicity*; D005982:Glutathione Transferase / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D005492:Folic Acid; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D005982:Glutathione Transferase