Effect of alcohol on cytochrome p450 arachidonic acid metabolism and blood pressure in rats and its modulation by red wine polyphenolics.
Alcohol-induced hypertension is well recognized with clear evidence for a direct pressor effect of chronic alcohol consumption provided by a number of intervention studies in humans. In experimental animals, the effect of alcohol on blood pressure is less consistent; however, in Sprague-Dawley rats, alcohol feeding consistently induces a hypertensive response. The mechanism of alcohol-induced hypertension is not clearly understood. Ethanol is known to induce certain cytochrome P450 (CYP) enzymes, particularly the 2E1 isoform, which has been shown to metabolise arachidonic acid (AA) to the 19-hydroxy metabolite (19-HETE), which could have pro-hypertensive activity; CYP4A, by comparison, is the principal AA omega-hydroxylase in the liver. Polyphenolic compounds, such as flavonoids, have been shown to inhibit some CYPs. 2. In this study, we determined the effect of alcohol administration on blood pressure and CYP-dependent AA metabolism in the rat and its possible modulation by red wine polyphenols. 3. Thirty male Sprague-Dawley rats were randomly allocated to three groups, which received water, low-dose ethanol (5% v/v) or red wine (diluted to contain 5% ethanol) for a period of 9 weeks. Bodyweight and blood pressure were measured weekly and 24h urine collected at baseline and every 2 weeks. Animals were killed at 9 weeks and blood and tissue samples were collected. The blood pressure of rats fed with alcohol increased significantly over the period of the study compared with controls (P<0.001). The blood pressure of animals fed 5% alcohol in the form of red wine was not significantly different from controls over the study period. The urinary excretion of 20-HETE did not differ significantly among the treatment groups over the study period and there was no effect of any treatment on the metabolism of AA by renal microsomes. Red wine, but not administration of the relatively low dose of alcohol alone, increased the expression of CYP2E1 protein in the liver and kidney and CYP4A in the kidney. Both red wine and alcohol decreased CYP4A protein levels in the liver compared with controls. 4. Our results suggest that constituents of red wine, possibly polyphenols, can attenuate the alcohol-induced rise in blood pressure in the Sprague-Dawley rat, although this effect does not appear to be mediated by the inhibition of CYP-derived AA metabolism.
School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia.
Christine
C
Cowpland
Gloria M
GM
Su
Michael
M
Murray
Ian B
IB
Puddey
Kevin D
KD
Croft
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects*; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D028421:Isoprostanes / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010636:Phenols / Q000494:pharmacology*; D059808:Polyphenols; D051381:Rats; D017207:Rats, Sprague-Dawley; D014920:Wine / Q000032:analysis*
D002492:Central Nervous System Depressants; D005419:Flavonoids; D006893:Hydroxyeicosatetraenoic Acids; D028421:Isoprostanes; D010636:Phenols; D059808:Polyphenols; D016718:Arachidonic Acid; D000431:Ethanol; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D042926:Cytochrome P-450 CYP4A