Growth and hepaticin vitrometabolism of ergotamine in mice divergently selected for response to endophyte toxicity

Abstract

This study investigated if genetic differences exhibited in endophyte-resistant and -susceptible mouse lines had persisted after 13 generations in which the integrity of lines was maintained yet selection ceased. Experimental groups were mouse lines fed an endophyte-free (E-) or -infected (E+) diet. The in vitro metabolism of the ergot alkaloid ergotamine in mouse liver microsomes was characterized by LC-MS/MS and compared between both lines before and after exposure to E+ feed. No difference in the average daily weight gain of pups between resistant and susceptible mice was observed on the E+ diet. Thus, for the weight gain selection criterion under study, the difference established between the two lines appears not to have persisted over the extended period of relaxed selection. Microsomal incubations produced nine predominate peaks in the HPLC assay. The peaks were confirmed by LC-MS/MS to be ergotamine, ergotamine epimer, monohydroxylated metabolites (M1, M2, M1e, M2e) and dihydroxylated metabolites (M3--5). A gender difference for metabolite formation was observed on the E- diet, in that females produced a greater amount of M1, M1e and M3--5 than males. When challenged with the E+ diet, mice showed differences in concentration of M3 for line (resistant > susceptible) and gender (female > male) and of M4 and M5 for gender (female > male). Gender differences in the metabolism of ergotamine have not been shown before in these lines of mice or other species used to study ergot alkaloid metabolism. This adds a potential source of variation in the susceptibility to fescue toxicity not explored previously and would be of value to investigate further.

Ergovaline in tall fescue and its effect on health, milk quality, biochemical parameters, oxidative status, and drug metabolizing enzymes of lactating ewes1

“…Erythromycin is a substrate of subfamily P450 3A, which is involved in the metabolism of ergot alkaloids, its inhibition leading to toxicity (Liaudet, 1999). Species and gender differences have been reported in in vitro metabolism of ergotamine, an alkaloid similar to EV, and it has been suggested that these differences could explain variations in sensitivity to fescue toxicosis (Duringer et al, 2005;Moubarak et al, 2006). Breed differences have also been cited to explain the differences in the prevalence of fescue toxicosis around the world.…”

Antineoplastic Activity of Monocrotaline Against Hepatocellular Carcinoma

“…The kupffer cells of liver regulate the inflammatory processes and promote liver cancer by expressing TREM1. The TREM-1 is involved in liver carcinogenesis due to chronic inflammation, which slowly develops into tumors that gradually metastasizes [14]. The inhibition of the TREM-1 signaling pathway can possibly be a rational target for clinical situations to manage human HCC [15].…”

“…HepG2 cell line showed expression of p53 by Western blotting [17]. HGF has an oncogenic potential in the generation of HCC observed from the molecular details of HepG2 cell line [14]. However, meager reports are available for TREM1 protein, which plays a crucial role in HCC.…”

Response to intensity of reproduction in mouse lines resistant or susceptible to fescue toxicosis

“…After eight generations of relaxed selection, however, growth rate from weaning to 3 months of age of S and R males was similarly affected by the toxin-containing diet (Ross et al 2004). Subsequently, after 15 generations of relaxed selection, the effect of the toxin-containing diet on postweaning gain was non-significantly greater in R than in S individuals (Duringer et al 2005). Thus, line differences for some traits related to toxin resistance may have been attenuated prior to initiation of the current experiment, reducing the potential for interaction between resistance mechanisms and intensity of reproduction.…”

“…2004). Subsequently, after 15 generations of relaxed selection, the effect of the toxin‐containing diet on postweaning gain was non‐significantly greater in R than in S individuals (Duringer et al. 2005).…”