Cannabinol and cannabidiol in combination: temperature, open-field activity, and vocalization

Rectal temperature as well as unconditioned activity in an open-field (O-F) arena, and palpation-induced vocalization were examined in rats treated intraperitoneally with cannabinol (CBN, 17.5 or 56 mg/kg) and cannabidiol (CBD, 10 or 30 mg/kg), either singly or in combination. CBN singly resulted in hypothermia which was not attenuated by the addition of CBD. CBN reduced ambulation and rearing activities as compared to vehicle-treated rats. CBD in combination with CBN did not attenuate these effects; the CBD doses in themselves appeared inactive. Vocalization occurred to a significantly greater extent in the CBN singly-treated rats as compared to the controls and the CBD singly-treated rats. Thus, CBD did not counteract the temperature and open-field effects induced by CBN. This is discussed in relation to previous results from drug discrimination experiments.     

Hypnoticlike effects of cannabidiol in the rat

The actions of cannabidiol (CBD), one of the cannabis constituents, were assessed on the sleep-wakefulness cycle of male Wistar rats.During acute experiments, single doses of 20 mg/kg CBD decreased slow-wave sleep (SWS) latency. After 40 mg/kg SWS time was significantly increased while wakefulness was decreased. REM sleep was not significantly modified. Following the once-daily injections of 40 mg/kg CBD for a period of 15 days, tolerance developed to all the above-mentioned effects.     

Extracellular ATP and UTP exert similar effects on rat isolated hepatocytes.

1. Extracellular UTP and ATP show obvious similarities in their control of several metabolic functions of rat isolated hepatocytes. 2. They have a similar time-course and concentration-dependency for the activation of glycogen phosphorylase, the generation of inositol trisphosphate (IP3), the inhibition of glycogen synthase and the lowering of adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 3. There is a similar synergism of the nucleotides with glucagon in activating phosphorylase. 4. They undergo a similar inhibition by phorbol myristic acid of their glycogenolytic effect. 5. The ATP and UTP effect on IP3 levels are not additive. 6. It is tentatively concluded that UTP and ATP use a common receptor.     

Estrogen and environmental estrogenic chemicals exert developmental effects on rat hypothalamic neurons and glias.

We investigated effects of 17beta-estradiol (E(2)) and endocrine disrupters, nonylphenol (NP) and bisphenol-A (BPA), focusing on the neuronal development in cultures of fetal rat hypothalamic cells. We applied different concentrations of E(2), NP or BPA to the cultured hypothalamic cells and observed their effects on dendritic and synaptic development by immunocytochemistry using anti-microtubule associated protein-2 (MAP2) and anti-synapsin I antibodies, respectively. Administration of E(2) for 7 days affected MAP2-positive area as well as synapsin I-positive area. NP and BPA also influenced neuronal developments. The significant increase both in MAP2- and synapsin I-positive areas was observed at 10 and/or 100 nM of them, while 1 microM of them reduced the positive areas. Synaptic densities calculated from synapsin I-positive area/MAP2-positive area were not constant among different doses of three chemicals, but increased at 10 and/or 100 nM and decreased at 1 microM. Furthermore, immunostaining of NP-treated cells with the antibody against glial fibrillary acidic protein (GFAP) revealed that glial development was similarly influenced by NP. Therefore, the present results demonstrated that not only E(2) but also the environmental estrogenic chemicals, NP and BPA, affect development of fetal rat hypothalamic cells in vitro.     

B-HT 920-induced effects on rat feeding behaviour.

Wistar rats, deprived of food for 15 h, were injected with B-HT 920 and 20 min later presented with their normal diet in their individual home cages. The parameters considered were latency to feeding and food intake which was determined 0.5, 1, 2, 3, 6 and 24 h later. B-HT 920 significantly reduced latency to feeding at 0.1, 0.5 and 1 mg/kg; food intake was increased by doses of 0.05 and 0.1 mg/kg 3 and 6 h after treatment and decreased by a dose of 1 mg/kg at 3 h. The amount of food eaten over a 24 h period by the various groups did not differ. At this time rats received a second injection of the drug at the same dosages, and preweighed food was presented again 20 min later. We confirmed that latency to feeding is lowered by B-HT 920 at 0.1, 0.5 and 1 mg/kg, doses which also induced feeding in sated rats within the first half-hour and even after 1 h in the case of the highest dose. Since penile erection and stretching and yawning, signs typically induced by all DA D2 agonists, were observed after B-HT 920 at 0.05, 0.1 and 0.5 mg/kg, discussion centres on the possible mechanisms involved in the B-HT 920-induced effects.     

2,5-hexanedione and carbendazim coexposure synergistically disrupts rat spermatogenesis despite opposing molecular effects on microtubules.

2,5-Hexanedione (2,5-HD), a taxol-like promoter of microtubule assembly, and carbendazim (CBZ), a colchicine-like inhibitor of microtubule assembly, are two environmental testicular toxicants that target and disrupt microtubule function in Sertoli cells. At the molecular level, these two toxicants have opposite effects on microtubule assembly, yet they share the common physiologic effect of inhibiting microtubule-dependent functions of Sertoli cells. By studying a combined exposure to 2,5-HD and CBZ, we sought to determine whether CBZ would antagonize or exacerbate the effects of an initial 2,5-HD exposure. In vitro, 2,5-HD-treated tubulin had a decreased lag time and an increased maximal velocity of microtubule assembly. These 2,5-HD-induced in vitro alterations in microtubule assembly were normalized by CBZ exposure. In vivo, adult male rats were exposed to a 1% solution of 2,5-HD in the drinking water for 2.5 weeks. CBZ was administered by gavage (200 mg/kg body weight) at the same time as unilateral surgical ligation of the efferent ducts, 24 h before evaluation of the testis. Measures of testicular effect (testis weight, histopathologic changes [sloughing and vacuolization], and seminiferous tubule diameters) were all significantly altered with combined exposure. The testicular effects in the combined exposure group were either different (seminiferous tubule diameters), additive (% vacuolization), or greater than additive (% sloughing) compared to the effects of the individual toxicant exposure groups referenced to the controls. Therefore, CBZ coexposure does not antagonize the effects of an initial 2,5-HD exposure, as might be expected if their molecular effects on microtubule assembly were solely responsible for their combined toxicity; instead, 2,5-HD and CBZ act together to exacerbate the testicular injury.     

Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability

BACKGROUND AND PURPOSE

Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro.

EXPERIMENTAL APPROACH

Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL⁻¹). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB₁, CB₂, TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids.

KEY RESULTS

Δ⁹-Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB₁ receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB₁ antagonism. No role for the CB₂ receptor was identified in these studies. Co-application of THC, cannabidiol or a CB₁ antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation.

CONCLUSIONS AND IMPLICATIONS

These findings suggest that locally produced endocannabinoids, acting via CB₁ receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation.

LINKED ARTICLES

This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7     

The opposing effects of endothelin-1 and C-type natriuretic peptide on apoptosis of neonatal rat cardiac myocytes

C-type natriuretic peptide (CNP) and endothelin-1 are paracrine peptides with opposing effects on cardiac myocyte contraction and intracellular cGMP production. Elevated levels of both endothelin-1 and CNP are found in patients with congestive heart failure. These factors may be related to positive and negative regulation of cell apoptosis in the failing heart. To evaluate the effect of CNP and endothelin-1 on apoptosis of cardiac myocytes and the possible mechanisms involved, primary cardiac myocytes were prepared from neonatal Sabra rats. Cardiomyocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Annexin V in situ staining. The TUNEL method was used to measure the apoptotic index. CNP and the cGMP derivative, 8-br-cGMP, induced apoptosis of cardiac myocytes. CNP-induced apoptosis could be blocked by HS 142-1 (a mixture of 20-30 kinds of linear beta-1, 6-glucan esterified by capronic acid, an antagonist of type A and B natriuretic peptide receptors), and KT 5823 (C29H25N3O5), the inhibitor of cGMP-dependent protein kinase). Alpha-difluoromethylornithine (DFMO), the irreversible inhibitor of ornithine decarboxylase, also induced apoptosis to a similar extent. CNP and 8-br-cGMP caused a marked reduction of intracellular ornithine decarboxylase expression, as determined by Western blot analysis and immunohistochemical assay. Preincubation with endothelin-1 attenuated CNP- and 8-br-cGMP-induced cardiomyocyte apoptosis. Endothelin-1 also antagonized the CNP- and 8-br-cGMP-induced reduction of intracellular ornithine decarboxylase expression. These results suggest that CNP has a proapoptotic effect on neonatal rat cardiac myocytes. The effect is mediated via natriuretic peptide receptors and is due to an elevation of intracellular cGMP, which reduces the expression of intracellular ornithine decarboxylase and probably the production of polyamines. Endothelin-1 protects cardiac myocytes against CNP-induced apoptosis by influencing the cGMP-dependent pathway, and this effect is probably mediated through both a reduction of cGMP and antagonism of the CNP-induced reduction of intracellular ornithine decarboxylase expression.     

Scopolamine and lorazepam exert different patterns of effects in a test battery assessing stages of information processing

The effects of a single dose of scopolamine (0.5 mg) SC and of lorazepam (2.5 mg) PO were tested in two independent studies for their effects on performance in a psychometric battery which measured functions related to different stages of information processing. Attention and vigilance were measured by a continuous attention task and a vigilance task, respectively. Working memory and reasoning were evaluated by the rapid information processing and logical reasoning task; memory acquisition and storage were measured by pre- and post-drug immediate and delayed recall using visual material. The following pattern of effects was revealed: both scopolamine and lorazepam impaired performance in attentional and vigilance tasks as well as in the rapid information processing task significantly (P<0.05) when compared with their own placebo; in the logical reasoning task lorazepam significantly prolonged the time required to solve a problem; scopolamine did not have any effect on this task. Scopolamine impaired performance in the immediate recall but left delayed recall unaffected; lorazepam impaired only delayed recall, immediate recall remaining unaffected. These data suggest that scopolamine at this dose impaired mostly attention and early stages of information processes; lorazepam at the dose tested impaired also the later acquisition and encoding aspects of memory.This article is part of the Doctoral Thesis of B. Redemann     

The effects of cannabidiol and tetrahydrocannabinol on motion-induced emesis in Suncus murinus

The effect of cannabinoids on motion-induced emesis is unknown. The present study investigated the action of phytocannabinoids against motion-induced emesis in Suncus murinus. Suncus murinus were injected intraperitoneally with either cannabidiol (CBD) (0.5, 1, 2, 5, 10, 20 and 40 mg/kg), Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 0.5, 3, 5 and 10 mg/kg) or vehicle 45 min. before exposure to a 10-min. horizontal motion stimulus (amplitude 40 mm, frequency 1 Hz). In further investigations, the CB(1) receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251; 5 mg/kg), was injected 15 min. prior to an injection of Delta(9)-THC (3 mg/kg). The motion stimulus was applied 45 min. later. The number of emetic episodes and latency of onset to the first emetic episode were recorded. Pre-treatment with the above doses of CBD did not modify the emetic response to the motion stimulus as compared to the vehicle-treated controls. Application of the higher doses of Delta(9)-THC induced emesis in its own right, which was inhibited by AM 251. Furthermore, pre-treatment with Delta(9)-THC dose-dependently attenuated motion-induced emesis, an effect that was inhibited by AM 251. AM 251 neither induced an emetic response nor modified motion-induced emesis. The present study indicates that Delta(9)-THC, acting via the CB(1) receptors, is anti-emetic to motion, and that CBD has no effect on motion-induced emesis in Suncus murinus.     

Different effects of nabilone and cannabidiol on binocular depth inversion in Man

The physiological and pathophysiological roles of the central nervous endogenous cannabinoid system are not completely understood, but still represent a challenge in basic neurobiological, cognitive, and psychiatric research. The system has been implicated in the pathogenesis of schizophrenia. Binocular depth inversion, an illusion of visual perception, provides a model of impaired perception during psychotic states. Using this model the effects of nabilone, a psychoactive synthetic 9-trans-ketocannabinoid, and of cannabidiol, the main natural component of herbal cannabis, and a combined application of both substances on binocular depth inversion and behavioural states were investigated in nine healthy male volunteers. The time course of the effects of both substances on binocular depth inversion was analysed after oral administration using three different groups of natural stimuli. A significant impairment of binocular depth perception was found when nabilone was administered, but combined application with cannabidiol revealed somewhat reduced effects on binocular depth inversion. The influence of psychoactive cannabinoids on this perceptual model and the role of the endogenous cannabinoid system in visual information processing are discussed.     

Lipoxygenase inhibitors exert secretagogue-specific effects on mast cell exocytosis

The lipoxygenase inhibitors HTYA (5,8,11,14-henicosatetraynoic acid, 25-150 microM) and ITYA (4,7,10,13-icosatetraynoic acid, 25-75 microM), inhibited histamine secretion from rat mast cells evoked by concanavalin A but that elicited by compound 48/80 or polymyxin B. Arachidonic acid (100 microM) did not inhibit concanavalin A-induced histamine secretion. The results are consistent with the notion that lipoxygenase inhibitors affect an early stage of stimulus-secretion coupling in the mast cell, peculiar to antibody-directed secretagogues, perhaps that involving calcium influx.     

In rat alveolar macrophages lipopolysaccharides exert divergent effects on the transport of the cationic amino acids l-arginine and l-ornithine

In rat alveolar macrophages (AMphi) it was tested whether induction of iNOS by lipopolysaccharides (LPS) is accompanied by changes in L-arginine transport and whether L-ornithine, the product of arginase released from AMphi, could, via inhibition of L-arginine uptake, act as a paracrine inhibitor of NO synthesis. Rat AMphi (cultured for 20 h in the absence or presence of 1 microg/ml LPS) were incubated in Krebs-HEPES solution containing [3H]-L-arginine (0.1 microM for 2 min or 100 microM for 5 min) and the cellular radioactivity was determined as a measure of L-arginine uptake. In parallel, cells were incubated for 6 h in Krebs-HEPES solution containing 0-1 mM L-arginine and nitrite accumulation was determined. [3H]-L-arginine uptake (0.1 microM or 100 microM) occurred independently of sodium ions and was inhibited by L-ornithine (EC50: 117 and 562 microM, respectively) and with similar potencies by L-lysine. In LPS-treated AMphi the concentration inhibition curve of L-ornithine was shifted to the right by about a factor of 4, whereas that of L-lysine was only marginally shifted to the right. L-Leucine (0.1 and 1 mM) inhibited [3H]-L-arginine (0.1 microM) by 43 and 58%, respectively, and the effect of 0.1 mM L-leucine was partially sodium dependent. In LPS-treated AMphi, 0.1 mM L-leucine no longer inhibited [3H]-L-arginine and the effect of 1 mM L-leucine was attenuated. Kinetic analysis of the transport of [3H]-L-arginine and [14C]-L-ornithine revealed two components for each amino acid with Km values of 21 and 114 microM (L-arginine) and 39 and 1050 microM (L-ornithine), respectively. After LPS treatment Km2 of L-arginine transport was reduced to 63 microM and Vmax of both components was increased, whereas Km2 of L-ornithine transport was enhanced to 1392 microM and Vmax1 reduced. LPS-stimulated AMphi, incubated in amino acid-free Krebs-HEPES solution, produced about 4 nmol nitrite/10(6) cells per 6 h, and L-arginine enhanced nitrite accumulation maximally about threefold (EC50: 30 microM). L-ornithine, up to 3 mM, failed to affect significantly nitrite accumulation observed in the presence of 30 or 100 microM L-arginine. Rat AMphi express mRNA for two cationic amino acid transporters (CAT-1 and CAT-2B), and LPS markedly up-regulated mRNA for CAT-2B in parallel with mRNA for iNOS, but had no effect on that for CAT-1. In conclusion, in rat AMphi LPS up-regulates L-arginine transport and induces changes in the characteristics of the cationic amino acid transport resulting in preferential transport of L-arginine. These effects may be regarded as cellular measures to ensure a high L-arginine supply for iNOS.     

Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism

Context: Soy is the main source of phytoestrogens, which has long been used as traditional food. One major subtype of phytoestrogens includes isoflavones and they are scientifically validated for their beneficial actions on many hormone-dependent conditions.

Objective: The present study examines the effect of soy isoflavones on letrozole-induced polycystic ovary syndrome (PCOS) rat model.

Materials and methods: PCOS was induced in Sprague–Dawley rats with of 1?mg/kg letrozole, p.o. once daily for 21 consecutive days. Soy isoflavones (50 and 100?mg/kg) was administered for 14 days after PCOS induction. Physical parameters (body weight, oestrous cycle determination, ovary and uterus weight) metabolic parameters (oral glucose tolerance test, total cholesterol), steroidal hormone profile (testosterone and 17β-oestradiol), steroidogenic enzymes (3β-hydroxy steroid dehydrogenase (HSD) and 17β-HSD), oxidative stress and histopathology of ovary were studied.

Results: Soy isoflavones (100?mg/kg) treatment significantly altered the letrozole-induced PCOS symptoms as observed by decreased body weight gain (p?p?p?p?p?Discussion: Treatment with soy isoflavones exerts beneficial effects in PCOS rats (with decreased aromatase activity) which might be due to their ability to decrease testosterone concentration in the peripheral blood.

Conclusion: Analysis of physical, biochemical and histological evidences shows that soy isoflavones may be beneficial in PCOS.     

Comparative metabolism of cannabidiol in dog, rat and man.

Urinary metabolites of cannabidiol (CBD) were extracted from human, dog and rat urine, concentrated by chromatography on Sephadex LH-20, and identified by GC/MS. Over 50 metabolites were identified with considerable species variation. CBD was excreted in substantial concentration from human urine, both in the free state and as its glucuronide. In dog, unusual glucoside conjugates of three metabolites (4'- and 5'-hydroxy and 6-oxo-CBD), not excreted in the unconjugated state, were found as the major metabolites at early times after drug administration. Other metabolites in all three species were mainly acids. Side-chain hydroxylated derivatives of CBD-7-oic acid were particularly abundant in human urine but much less so in dog. In the latter species the major oxidized metabolites were the products of beta-oxidation with further hydroxylation at C-6. A related, but undefined pathway, resulted in loss of three carbon atoms from the side-chain of CBD in man with the production of 2'-hydroxy-tris,nor-CBD-7-oic acid. Previous experiments indicate that 3'-hydroxy-metabolites are the precursors of compounds having this side-chain. Metabolism by the epoxide-diol pathway, resulting in dihydro-diol formation from the delta-8-double bond, gave metabolites in both dog and human urine. It was concluded that CBD could be used as a probe of the mechanism of several types of biotransformation, particularly those related to carboxylic acid metabolism, as intermediates of the type not usually seen with endogenous compounds were excreted in substantial concentration.     

The effects of cannabidiol on male reproductive system: A literature review

Cannabidiol (CBD) is one of the most abundant phytocannabinoids present in the plant Cannabis sativa (marijuana). There have been several studies of CBD in the last few decades, mainly focused on its neuroprotective properties, particularly after the identification of the endocannabinoid system and its participation in the central nervous system. On the other hand, the peripheral effects of CBD, particularly on reproductive physiology, were also evidenced. A narrative review was conducted using the PubMed database to identify studies that analyzed the pharmacological effects of CBD on the male reproductive system of vertebrates and invertebrates. Thirty-two citations (in vivo and in vitro) were identified. Among the vertebrates, the studies were carried out with men, monkeys, rats and mice. Studies with invertebrates are centered exclusively on the sea urchin. The CBD treatment periods include mostly acute and subacute evaluations. Exposure to CBD is associated with a reduction in mammalian testis size, the number of germ and Sertoli cells in spermatogenesis, fertilization rates, and plasma concentrations of hypothalamic, pituitary and gonadal hormones. Moreover, chronic doses of CBD have impaired sexual behavior in mice. From the studies identified in this review, it is possible to conclude that CBD has negative effects on the reproductive system of males. However, knowledge is still limited, and additional research is required to elucidate fully the mechanisms of action, as well as the reversibility of CBD effects on the reproductive system.     

Safety and side effects of cannabidiol, a Cannabis sativa constituent

Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.     

Short-chain fatty acids exert opposite effects on the expression and function of p-glycoprotein and breast cancer resistance protein in rat intestine

P-glycoprotein(P-gp)and breast cancer resistance protein(BCRP)are involved in intestinal barrier.Short-chain fatty acids(SCFAs)play important roles in maintaining intestinal barrier.In this study we explored how SCFAs affected the expression and function of intestinal P-gp and BCRP in rats.Rats received 150 mM acetate,propionate or butyrate in drinking water for 4 weeks.In SCFA-treated rats,the expression and function of intestinal P-gp were decreased,but those of intestinal BCRP were increased;intestinal p-p65 was also decreased,which was positively related to P-gp protein expression.Among the three SCFAs tested,butyrate exhibited the strongest induction or inhibitory effect,followed by propionate and acetate.Similar results were observed in mouse primary enterocytes and Caco-2 cells treated with acetate(5 mM),propionate(2 mM),or butyrate(1 mM).In Caco-2 cells,addition of butyrate,vorinostat,and valproate(two classic HDAC inhibitors),Bay117082(selective inhibitor of NF-κB activation)or NF-κB p65 silencing significantly decreased the expression of P-gp and the level of phosphorylated p65(p-p65).Furthermore,butyrate attenuated the expression of P-gp and p-p65 induced by TNF-α(NF-κB activator)and theophylline(HDAC activator).However,vorinostat,valproate,Bay117082,TNF-αor p65 silencing hardly affected BCRP protein expression.But GW9662(selective PPARγantagonist)or PPARγsilencing abolished BCRP induction by butyrate and troglitazone(PPARγagonist).SCFAs-treated rats showed higher intestinal protein expression of PPARγ,which was positively related to BCRP protein expression.Butyrate increased plasma exposure of fexofenadine but decreased that of rosuvastatin following oral dose to rats.In conclusion,SCFAs exert opposite effects on the expression and function of intestinal P-gp and BCRP;butyrate downregulated P-gp expression and function possibly via inhibiting HDAC/NF-κB pathways;butyrate induced BCRP expression and function partly via PPARγactivation.