Phase 1 and phase 2 metabolic activities along the small intestine in adult male sheep1

Abstract

Metabolic activities of several xenobiotic metabolizing enzymes were evaluated in both hepatic and enteric subcellular fractions obtained from Corriedale × Merino crossbreed rams by using a biochemical approach. Microsomes obtained from the different segments of sheep small intestinal mucosa displayed cytochrome P450 (CYP)-dependent N-demethylations but not O-deethylase activities apparently occurred. CYP-mediated N-demethylations neither decreased nor increased along the small intestinal mucosa. Percentages of activity for erythromycin N-demethylase in the small intestine were between 29% (duodenum) and 45% (ileum) from that measured in the liver, whereas those determined for triacetyl-oleandomycin N-demethylation ranged between 10% (duodenum) and 15% (jejunum) of the same hepatic activity. Conversely, metabolic rates for aminopyrine and chlorfeniramine N-demethylations in the gut mucosa ranged between 3% and 7% compared to their respective hepatic enzyme activities. Sheep enteric mucosa also displayed metabolic reactions typically mediated by flavin-containing monooxygenases (FMOs), carbonyl reductases (CBRs), carboxylesterases (CES), glutathione S-transferases (GSTs) and uridine diphosphoglucuronyltransferases (UGTs). The FMO-mediated sulfoxidation of methimazole was 2.6-fold higher (P < 0.01) in the ileal compared to the duodenal mucosa. Percentages of activity for the microsomal CBR-dependent biotransformation of menadione were between 12% (ileum) and 19% (duodenum-jejunum) of the total activity measured in the liver; metabolic rates measured in duodenum and jejunum were ∼1.7-fold higher (P < 0.05) than that observed in the ileum. The microsomal CES activity (using p-nitrophenyl acetate as substrate) was around twofold higher in duodenum (P < 0.05) and jejunum (P < 0.01) in comparison to the ileum. Cytosolic GST-dependent activities (toward 1-chloro, 2,4-dinitrobenzene) were similar in the mucosa of duodenum, jejunum and ileum. Microsomal UGT activities (toward 1-naphthol) in duodenum and jejunum were three- and fourfold higher, respectively, compared to that measured in the ileum. The small intestinal mucosa may play a critical defensive role due to its involvement in the detoxification of toxic compounds prior to absorption. In addition, gut metabolic reactions may contribute to the presystemic metabolism of orally administered drugs. These results are a further contribution to the understanding of the relevance of the extra-hepatic metabolism of xenobiotics in ruminant species.

Neurochemical characterization of the enteric neurons within the porcine jejunum in physiological conditions and under the influence of bisphenol A (BPA)

“…The jejunum is a fragment of the digestive tract, where the majority of BPA is glucuronidated and absorbed . Previous studies have reported that glucuronide and glucuronidated BPA have low estrogenic activity, and some studies have suggested that the proximal part of the jejunum may play a defensive role against the toxicological impact of bisphenol A in food . It is also known that the action of BPA on the jejunum may take place by the direct influence of BPA on the mucosal layer of the intestine, as well as by the impact of the toxin penetrating the jejunal wall with blood.…”

In vitro and in vivo effects of chlorpyrifos and cypermethrin on blood cholinesterases in sheep

“…). Moreover, the rate of conjugation of this substrate resulted much higher in sheep liver (1,750 nmol min −1 mg −1 ;Maté et al, 2010) compared with that measured in cattle (around 250 nmol min −1 mg −1 ;…”

“…Compared with other livestock species, cattle exhibited considerably lower efficiency in the GST‐dependent conjugation of CDNB (a general substrate for all GST classes) (Gusson, Carletti, Albo, Dacasto, & Nebbia, ). Moreover, the rate of conjugation of this substrate resulted much higher in sheep liver (1,750 nmol min −1 mg −1 ; Maté et al, ) compared with that measured in cattle (around 250 nmol min −1 mg −1 ; Gusson et al, ). Accordingly, a higher efficiency for CPF and CPF oxon detoxification could be expected in sheep compared with cattle and may contribute to the aforementioned species differences in the pattern of blood AChE and BChE inhibition under in vivo conditions.…”

Cytochrome P450 3A expression and function in liver and intestinal mucosa from dexamethasone‐treated sheep

“…The intestinal mucosa of ruminants also displays a CYP3A‐dependent metabolism (Dupuy et al. , 2001; Maté et al. , 2010; Virkel et al.…”

“…The rates of the in vitro N‐demethylations of triacetyl‐oleandomycin (TAO) and ERTM were measured for the evaluation of CYP3A‐dependent metabolism in liver microsomal preparations, whereas only ERTM N‐demethylase activity was assayed in microsomes obtained from the small intestine. Enzyme assays were carried out under aerobic conditions as previously described (Maté et al. , 2010).…”