Suppression of Cytochrome P450- and UDP Glucuronosyl Transferase-Dependent Enzyme Activities by Proinflammatory Cytokines and Possible Role of Nitric Oxide in Primary Cultures of Pig Hepatocytes

Monshouwer, Mario; Witkamp, Renger F.; Nijmeijer, S. M.; Amsterdam, J.G. van; Miert, A. S. J. P. A. M. van

doi:10.1006/taap.1996.0077

Cited by 106 publications

(63 citation statements)

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“…[20][21][22] Lambert et al 20) reported that the total hepatic CYP content declined 41% in dogs with congestive HF. Fradette et al 21) evaluated the effect of hypoxemia on P450 expression in rabbit hepatocytes, and reported that the expression of CYP1A1 and 1A2 in rabbits with hypoxia was 63% and 60%, respectively, of that in control rabbits.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Horiuchi

Nozawa

Fujii

et al. 2008

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist, clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1) Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.2) Carvedilol is metabolized extensively via aliphatic sidechain oxidation, aromatic ring oxidation, and conjugation pathways.3) Oldham and Clarke 4) reported that oxidative activity for carvedilol is observed in cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2. In addition, Ohno et al. 5) reported that UDP-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol. In the previous study, we examined the effect of CYP2D6*10, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 on the pharmacokinetics of carvedilol in 54 Japanese volunteers. 2,6) The oral clearance (CL/F) and also volume of distribution (V/F) of R-and S-carvedilol were significantly lower in subjects with the CYP2D6*10 allele than those with CYP2D6*1/*1, *1/*2, or *2/*2 genotype, indicating that the systemic clearance (CL) and/or bioavailability (F) of both enantiomers is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 did not affect the pharmacokinetics of R-and S-carvedilol in healthy Japanese. 2,6) Several pharmacokinetic studies have suggested that hepatic elimination of certain drugs via oxidative metabolism is impaired in patients with heart failure (HF) [7][8][9][10][11][12][13] ; that is, the CL/F value of prazosin after oral administration in HF patients was 46% of that in healthy subjects.7) It was also reported that the CL/F value of aminopyrine after oral administration in HF patients in the aminopyrine breath test was 24% of that in control subjects. 8) In addition, CL values of midazolam and quinidine (CYP3A4 substrates) after intravenous administration were decreased by 32% and 33% in HF patients, respectively. 9,10) The CL value of theophylline (CYP1A2 substrate) after intravenous administration was markedly decreased in HF patients. 11,12) Recently, population pharmacokinetic analysis has revealed that the CL/F value of mexiletine, which is mainly metabolized by CYP1A2 and CYP2D6, is reduced significantly in HF patients as compared with non-HF patients.13) However, it is still unclear whether the pharmacokinetics of R-and/or S-carvedilol is altered by HF. In the present study, therefore, we investigated the pharmacokinetics of R-and S-carvedilol in routinely treated Japanese patients with HF. MATERIALS AND METHODS Subjects and Study ProtocolTwenty-four Japanese patients with HF (16 men and 8 women) participated in this study. Their age was between 45 and 91 years old (70.5Ϯ11.3 years), and their body weight was between 36...

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Section: Discussionmentioning

confidence: 99%

“…They also reported that serum mediators such as interferon-a, interleukin (IL)-1b, and IL-2 contributed to the change in the expression of several CYP enzymes. 21) In addition, Monshouwer et al 22) reported that not only CYP but also UGT activity of pig hepatocytes was attenuated by recombinant human IL-1a, IL-6, and tumor necrosis factora.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Horiuchi

Nozawa

Fujii

et al. 2008

Biological & Pharmaceutical Bulletin

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“…It is assumed that the activation of liver macrophages (Kupffer cells) is an important factor in the dysfunctioning of the liver during inflammation (8,20,21). Substantial research on the effect on drug dispostion and metabolism has been investigated in vitro and in vivo using porcine models of infection and inflammation (23)(24)(25)28). Therefore primary macrophages were isolated from pigs (lung and liver) to test the in vitro anti-inflammatory effects of phosphodiesterase-IV-(PDE-IV)-inhibitors (pentoxifylline and rolipram) and B-adrenoceptor agonists (clenbuterol and salbutamol).…”

Section: Introductionmentioning

confidence: 99%

Suppression of the acute inflammatory response of porcine alveolar‐ and liver macrophages

Izeboud¹,

Monshouwer

Witkamp

et al. 2000

Veterinary Quarterly

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During infection and inflammation drug disposition and hepatic metabolism are markedly affected in mammals. Pro-inflammatory mediators play an important role in the suppression of (cytochrome-P450-mediated) drug metabolism. Inflammatory mediators like cytokines, nitric oxide (NO), reactive oxygen species (ROS) and eicosanoids are released by activated macrophages from various sources, including liver and lung. It was the aim of this study to investigate ways to suppress the activation of macrophages during the onset of the inflammatory cascade. Therefore porcine lung and liver macrophages were isolated, and incubated with lipopolysaccharide (LPS) to initiate an acute inflammatory response, represented by the release of high amounts of tumour necrosis factor-a (TNF-a) into the culture medium. Additionally the primary macrophages were coincubated with phosphodiesterase-IV-(PDE-IV)-inhibitors or B-adrenoceptor agonists that in previous studies demonstrated strong suppressive effects on TNF-a release. Especially the B-adrenoceptor agonists showed to be very potent TNF-a suppressants, which indicates that the B-adrenoceptor might be an interesting target for suppression of activation of macrophages. This was strengthened by the observation that the B-adrenoceptor expression was not altered during the onset of the inflammatory cascade.

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“…IL-1␤, IL-6) is believed to result from the repression of genes that normally mediated the hepatic uptake, metabolism, and biliary excretion of bile salts and various nonbile salt organic anions such as bilirubin (12,13). In addition, IL-1␣, IL-6, and tumor necrosis factor (TNF)-␣ were found to decrease the glucuronidation activities dose dependently (14).…”

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confidence: 99%

Cytokines in Human Colostrum and Neonatal Jaundice

et al. 2007

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Breast-fed infants have higher bilirubin levels than formula-fed infants, possibly because of variations in the composition of the breast milk. The aim of this study was to investigate whether there is a relationship between cytokine levels in the colostrum of nursing mothers and neonatal jaundice (NJ). Breast milk samples were collected from breast-feeding mothers of healthy fullterm neonates, 32 with NJ and 29 without jaundice. The concentrations of IL-1␤, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-␣ were measured by chemiluminescence enzyme immunometric assays. Mothers of infants with NJ had a higher concentration of IL-1␤ in colostrum, compared with those feeding neonates without NJ, and similar trends were seen for IL-6, IL-8, IL-10, and for TNF-␣. The concentrations of IL-1␤ significantly correlated with IL-6, IL-8, IL-10, and TNF-␣ concentrations, but not with serum bilirubin levels of infants with NJ. In conclusion, the concentrations of IL-1␤ were increased in colostrum from breast-feeding mothers whose infants had NJ. The correlation between the concentrations of cytokines involved in the function of hepatic uptake and excretory systems and in the enterohepatic circulation of bilirubin provides additional data to the delineation of the cascade of pathophysiological events that can lead to NJ. B reast-fed infants have higher bilirubin levels than formula-fed infants (1). The jaundice of breast-fed infants is commonly of undetermined etiology (2-4). Suggested mechanisms for these findings include insufficient milk transfer to the neonate (5), inhibition of hepatic excretion of bilirubin (6), and increased intestinal absorption of bilirubin (7,8).Inhibition of hepatic excretion of bilirubin could explain the jaundice associated with human milk consumption, and early studies suggested that exposure to acquired cholestatic injury such as drugs, hormones, proinflammatory cytokines, or biliary obstruction or destruction results in an altered expression and function of hepatic uptake and excretory systems, changes that may maintain and contribute to cholestasis and jaundice (9). In particular, increased production of IL-8 and IL-10 has been reported in patients with biliary obstruction and jaundice (10,11). Moreover, the cholestatic effect of cytokines (e.g. IL-1␤, IL-6) is believed to result from the repression of genes that normally mediated the hepatic uptake, metabolism, and biliary excretion of bile salts and various nonbile salt organic anions such as bilirubin (12,13). In addition, IL-1␣, IL-6, and tumor necrosis factor (TNF)-␣ were found to decrease the glucuronidation activities dose dependently (14).Intestinal absorption is a key step in the enterohepatic circulation of bilirubin because bilirubin is more easily absorbed from the intestine than are bilirubin glucuronides. Increased intestinal absorption of bilirubin (15), facilitated by breast milk rich in ␤-glucuronidase (16) or via some other mechanisms such as delayed passage of meconium, the establishment of a population of inte...

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Suppression of Cytochrome P450- and UDP Glucuronosyl Transferase-Dependent Enzyme Activities by Proinflammatory Cytokines and Possible Role of Nitric Oxide in Primary Cultures of Pig Hepatocytes

Cited by 106 publications

References 0 publications

Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Pharmacokinetics of R- and S-Carvedilol in Routinely Treated Japanese Patients with Heart Failure

Suppression of the acute inflammatory response of porcine alveolar‐ and liver macrophages

Cytokines in Human Colostrum and Neonatal Jaundice

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