Effect of ergot alkaloids associated with fescue toxicosis on hepatic cytochrome P450 and antioxidant proteins.
Intake of ergot alkaloids found in endophyte-infected tall fescue grass is associated with decreased feed intake and reduction in body weight gain. The liver is one of the target organs of fescue toxicosis with upregulation of genes involved in xenobiotic metabolism and downregulation of genes associated with antioxidant pathways. It was hypothesized that short-term exposure of rats to ergot alkaloids would change hepatic cytochrome P450 (CYP) and antioxidant expression, as well as reduce antioxidant enzyme activity and hepatocellular proliferation rates. Hepatic gene expression of various CYPs, selected nuclear receptors associated with the CYP induction, and antioxidant enzymes were measured using real-time PCR. Hepatic expression of CYP, antioxidant and proliferating cell nuclear antigen (PCNA) proteins were measured using Western blots. The CYP3A1 protein expression was evaluated using primary rat hepatocellular cultures treated with ergovaline, one of the major ergot alkaloids produced by fescue endophyte, in order to assess the direct role of ergot alkaloids in CYP induction. The enzyme activities of selected antioxidants were assayed spectrophotometrically. While hepatic CYP and nuclear receptor expression were increased in ergot alkaloid-exposed rats, the expression and activity of antioxidant enzymes were reduced. This could potentially lead to increased oxidative stress, which might be responsible for the decrease in hepatocellular proliferation after ergot alkaloid exposure. This study demonstrated that even short-term exposure to ergot alkaloids can potentially induce hepatic oxidative stress which can contribute to the pathogenesis of fescue toxicosis.
Settivari
Raja S
RS
Division of Animal Science, University of Missouri, Columbia, MO 65211, USA.
Evans
Tim J
TJ
Rucker
Ed
E
Rottinghaus
George E
GE
Spiers
Donald E
DE
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004876:Ergot Alkaloids / Q000633:toxicity*; D004879:Ergotamines / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008129:Lolium / Q000633:toxicity*; D008297:Male; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism; D047488:Retinoid X Receptors / Q000187:drug effects / Q000378:metabolism
D004876:Ergot Alkaloids; D004879:Ergotamines; D007527:Isoenzymes; D000077297:Pregnane X Receptor; D018809:Proliferating Cell Nuclear Antigen; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; C076760:ergovaline; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases