Relationships among ergot alkaloids, cytochrome P450 activity, and beef steer growth

Rosenkrans, C. F.; Ezell, Nicholas S.

doi:10.3389/fchem.2015.00016

Cited by 7 publications

(12 citation statements)

References 26 publications

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“…Vasoconstrictive responses (Klotz et al, 2008;Oliver et al, 1993;Oliver et al, 1998;Rhodes et al, 1991) inducing perturbed nutrient absorption and metabolism (Egert et al, 2014a;Pesqueira et al, 2014) occur concurrently with altered circulating prolactin and cholesterol levels, which together with and intra-and extrahepatic enzyme activity changes, may play a role in the etiology of FT (Bacon, 1995;Rosenkrans and Ezell, 2015;Settivari et al, 2008;Thompson and Stuedemann, 1993;Zbib et al, 2014Zbib et al, , 2015. Foote et al (2013) suggested impaired weight gain might be attributed to a decrease in volatile fatty acid (VFA) absorption or production caused by increased ruminal EA concentration.…”

Section: A N U S C R I P Tmentioning

confidence: 97%

Metabolomics of fescue toxicosis in grazing beef steers

Mote

Hill

Uppal

et al. 2017

Food and Chemical Toxicology

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Fescue toxicosis (FT) results from consumption of tall fescue (Lolium arundinaceum) infected with an endophyte (Epichloë coenophiala) that produces ergot alkaloids (EA), which are considered key etiological agents of FT. Decreased weight gains, hormonal imbalance, circulating cholesterol disruption, and decreased volatile fatty acid absorption suggest toxic (E+) fescue-induced metabolic perturbations. Employing untargeted high-resolution metabolomics (HRM) to analyze E+ grazing-induced plasma and urine metabolome changes, fescue-naïve Angus steers were placed on E+ or non-toxic (Max-Q) fescue pastures and plasma and urine were sampled before, 1, 2, 14, and 28 days after pasture assignment. Plasma and urine catecholamines and urinary EA concentrations were also measured. In E+ steers, urinary EA appeared early and peaked at 14 days. 13,090 urinary and 20,908 plasma HRM features were detected; the most significant effects were observed earlier (2 days) in the urine and later (≥14 days) in the plasma. Alongside EA metabolite detection, tryptophan and lipid metabolism disruption were among the main consequences of E+ consumption. The E+ grazing-associated metabolic pathways and signatures described herein may accelerate development of novel early FT detection and treatment strategies.

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Section: A N U S C R I P Tmentioning

confidence: 97%

Metabolomics of fescue toxicosis in grazing beef steers

Mote

Hill

Uppal

et al. 2017

Food and Chemical Toxicology

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“…Bovine CYP3A (bCYP3A) enzymes are involved in the metabolism of a number of drugs widely used in farming such as the macrocyclic lactone moxidectin 19 , tiamulin and macrolide antibiotics 20 as well as the ionophore monensin 21 . Moreover, bCYP3As are involved in the bioactivation of important natural toxins like aflatoxins and ergot alkaloids 22,23 . Three main b CYP3A genes have been identified, and a new nomenclature, mirroring the true evolutionary relationships among bCYP isoforms has been proposed: CYP3A28 (orthologue of human CYP3A4 ), CYP3A38 (orthologue of human CYP3A5 ) and CYP3A48 (corresponding to “b CYP3A4 nifedipine oxidase”) 24 .…”

Section: Introductionmentioning

confidence: 99%

Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle

Giantin

Rahnasto-Rilla

Tolosi

et al. 2019

Sci Rep

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Cytochrome P450 3A is the most important CYP subfamily in humans, and CYP3A4/CYP3A5 genetic variants contribute to inter-individual variability in drug metabolism. However, no information is available for bovine CYP3A (bCYP3A). Here we described bCYP3A missense single nucleotide variants (SNVs) and evaluated their functional effects. CYP3A28, CYP3A38 and CYP3A48 missense SNVs were identified in 300 bulls of Piedmontese breed through targeted sequencing. Wild-type and mutant bCYP3A cDNAs were cloned and expressed in V79 cells. CYP3A-dependent oxidative metabolism of testosterone (TST) and nifedipine (NIF) was assessed by LC-MS/MS. Finally, SNVs functional impact on TST hydroxylation was measured ex vivo in liver microsomes from individually genotyped animals. Thirteen missense SNVs were identified and validated. Five variants showed differences in CYP3A catalytic activity: three CYP3A28 SNVs reduced TST 6β-hydroxylation; one CYP3A38 variant increased TST 16β-hydroxylation, while a CYP3A48 SNV showed enhanced NIF oxidation. Individuals homozygous for rs384467435 SNV showed a reduced TST 6β-hydroxylation. Molecular modelling showed that most of SNVs were distal to CYP3A active site, suggesting indirect effects on the catalytic activity. Collectively, these findings demonstrate the importance of pharmacogenetics studies in veterinary species and suggest bCYP3A genotype variation might affect the fate of xenobiotics in food-producing species such as cattle.

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“…Furthermore, they are responsible for the bioactivation of natural toxins of current growing interest, i.e. aflatoxins and ergot alkaloids (Kuilman et al 2000;Sales et al 2012;Rosenkrans and Ezell 2015).…”

Section: Introductionmentioning

confidence: 99%

Missense single nucleotide variants affecting CYP3A catalytic activity are present in Limousine cattle

Pauletto

Tolosi

Dacasto

et al. 2020

Italian Journal of Animal Science

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Cytochrome P450 (CYP) 3A is one of the most important subfamily of drug metabolising enzymes. Genetic factors such as breed and allelic variants might modify CYP3A expression and enzyme activity and lead to inter-and intra-individual variability in clinical response or toxicity. Cattle CYP3A gene cluster has been recently re-sequenced in 300 Piedmontese cattle by deep targeted sequencing. Thirteen missense single nucleotide variants (SNVs) were identified, and for five of them an impact on CYP3A activity was demonstrated in vitro. In the present work, we assessed the genetic frequency of these five SNVs in Limousine, a cattle breed widely raised for meat production in Veneto Region. A total of 215 cows were genotyped using specific melting curve assays. Only two missense SNVs out of five, both located on CYP3A28 coding sequence, were detected: rs384467435 and rs454167819. The former mutant allele was present in homozygosis in the 4% of tested cows, while in heterozygosis in the 24% of animals. The second SNV was detected only in heterozygosis in 11 cows out of 215 (i.e. 4.9%). These findings suggest the presence of missense SNVs, proved to halve CYP3A28 catalytic activity, in both Limousine and Piedmontese meat cattle breeds. As a consequence, these SNVs might impact on the kinetics of xenobiotics metabolised by CYP3A, including drugs and natural toxins like ivermectin and aflatoxins, thereby resulting in toxicity or accumulation of harmful residues in foodstuffs. This result paves the way for new considerations on the fate of xenobiotics in cattle farming. HIGHLIGHTS Missense single nucleotide variants affecting CYP3A catalytic activity in vitro are present in Limousine and Piedmontese cattle breeds. Rs384467435 is the only missense single nucleotide variant for which the mutant allele is recorded in homozygosis in approximately 4% of Limousine and Piedmontese cattle. The polymorphisms here detected might affect the kinetics and the toxicity of xenobiotics metabolised by CYP3A in cattle.

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Relationships among ergot alkaloids, cytochrome P450 activity, and beef steer growth

Cited by 7 publications

References 26 publications

Metabolomics of fescue toxicosis in grazing beef steers

Metabolomics of fescue toxicosis in grazing beef steers

Functional impact of cytochrome P450 3A (CYP3A) missense variants in cattle

Missense single nucleotide variants affecting CYP3A catalytic activity are present in Limousine cattle

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