1 To investigate the e ect of moderate hypoxia alone or combined with an in¯ammatory reaction or after 3-methylcholanthrene (3MC) pre-treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O 2 of 10% (mean PaO 2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (Cl M ) from 1.73+0.43 to 1.48+0.13 ml min 71 kg 71 (P50.05), and reduced (P50.05) the formation clearance of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU) and 1,3-dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. 2 Turpentine-induced in¯ammatory reaction reduced (P50.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, in¯ammation partially prevented the decrease in Cl M , especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. 3 Pre-treatment with 3MC augmented the Cl M by 114% (P50.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre-treatment with 3MC prevented the hypoxia-induced decrease in amount and activity of the P450. 4 It is concluded that acute moderate hypoxia and an in¯ammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the in¯ammatory reaction restores P450 activity to near normal values. On the other hand, pretreatment with 3MC prevents the hypoxia-induced depression of the P450.
1 Infection and in¯ammation trigger a cascade of mediators that eventually will down-regulate the hepatic cytochrome P450 (P450). The present study aimed to characterize the mediators contained in the serum of rabbits with an acute in¯ammatory reaction (AIR) induced by the s.c. injection of turpentine (5 ml), and in the serum of humans with an acute upper respiratory tract viral infection. 2 Hepatocytes from control (H CONT ) rabbits and rabbits with an AIR (H INFLA ) were isolated and cultured. Compared with H CONT in H INFLA the production of theophylline metabolites, 3-methylxanthine (3MX), 1-methyluric acid (1MU), and 1,3-dimethyluric acid (1,3DMU) was reduced as was the amount of total P450, while lipid peroxidation was increased. Incubation of H INFLA with serum of rabbits with an AIR (RS INFLA ) for 4 h further reduced the formation of the metabolites of theophylline as well as the amount of P450, and enhanced the lipid peroxidation. RS INFLA obtained 6, 12 and 24 h after the injection of turpentine showed the same ability to down-regulate hepatic P450 as the serum obtained at 48 h. 3 The e cacy (E max ) of RS INFLA to inhibit the formation of theophylline metabolites di ered, i.e. 1,3DMU41MU43MX, and the potency of serum mediators (IC 50 ) was similar for 3MX and 1MU, but lower for 1,3DMU. 4 Incubation of serum of human volunteers (HS INFLA ) with a viral infection with H CONT or H INFLA reduced the production of theophylline metabolites, as well as the amount of P450, and increased the lipid peroxidation. HS INFLA depressed 1,3DMU more e ciently than 3MX and 1MU. HS INFLA reduced 3MX with greater e cacy than did RS INFLA . Potency was very variable but not di erent from rabbits. 5 It is concluded that the serum of rabbits with an AIR or of humans with a viral infection contain several mediators that inhibit noncompetitively various isoenzymes of the hepatic P450. The decrease in P450 induced by HS INFLA or RS INFLA is closely associated with the increase in lipid peroxidation (r 2 = 0.8870) suggesting that lipid peroxidation could directly or indirectly be involved in the P450 downregulation.
1 Serum from humans with an acute upper respiratory viral infection and from rabbits with turpentine-induced in¯ammation reduce the catalytic activity of hepatic cytochrome P450 (P450). The aim of this study was to identify the serum mediators responsible for the decrease in P450 activity. 2 Rabbit and human sera were fractionated by size exclusion chromatography and the fractions tested for their ability to reduce the activity and amount of P450 after 4 h of incubation with hepatocytes from turpentine-treated rabbits (H INF ). Rabbit and human sera decreased P450 activity by around 40% without any change in the amount of CYP1A1 and 1A2 apoproteins. 3 In rabbit serum, the fraction containing proteins of M r 23 ± 15 kDa decreased P450 content by 41%, but did not alter the amount of the apoproteins. Anti-IL-6 antibody added to the M r 23 ± 15 kDa fraction restored P450 content to 97% of control values, while anti-IL-1b, TNF-a and IFNg antibodies had no e ect. Supporting the role of IL-6, incubation of H INF in the presence of IL-6 for 4 h reduced P450 content by 40%. 4 In human serum, the fraction containing proteins of M r 495 kDa lowered P450 content by 43% without modifying the amounts of CYP1A1/2. Neutralization experiments showed that IFN-g, IL-6, and IL-1b contributed to the decrease in P450 content. 5 In conclusion, the present results demonstrate that IL-6, and IFN-g, IL-6 and IL-1b are the serum mediators released in vivo by a turpentine-induced in¯ammatory reaction in the rabbit and an upper respiratory viral infection in humans, respectively, inactivating hepatic P450.
In humans, oral bioavailability of nifedipine has been reported to be around 60%, although the organ(s) contributing to its first-pass metabolism have not been determined. The aim of this study was to determine in vivo, in anesthetized and conscious rabbits the role of the intestine, liver, and lungs in the first-pass metabolism of nifedipine. To assess the extraction of nifedipine by the intestine, liver, and lungs, nifedipine was administered before and after each organ, and serial blood samples were withdrawn from an artery. In conscious rabbits, the systemic clearance of nifedipine injected into a lateral vein of an ear was 14.6 +/- 1.6 ml/min per kg, a value that was slightly decreased by anesthesia. In anesthetized rabbits, compared to the clearance estimated when nifedipine was administered into the thoracic aorta, the administration of nifedipine into a jugular vein, into the portal vein, or into the portal vein, or into the duodenum did not increase the value of the systemic clearance. In conscious rabbits, the clearance of nifedipine estimated when the drug was administered into the duodenum, the peritoneum, the portal vein, or into the jugular vein was identical to the clearance calculated when the drug was injected into the thoracic aorta. In vitro, nifedipine was metabolized in liver and intestinal epithelial cells homogenates but not in lungs or kidneys. We concluded that in the rabbit, oral nifedipine is not subjected to a first-pass metabolism, even though the intestine and the liver may contribute to nifedipine systemic clearance.
Frusemide is removed from the body by biotransformation and renal secretion, but since frusemide metabolism is not altered in patients with hepatic cirrhosis, the role of the liver may be questioned. The aim of the study was to investigate which organs contribute to the first‐pass metabolism and systemic clearance of frusemide. Groups of anaesthetized New Zealand rabbits were administered frusemide proximally (prox) and distally (dist) to different organs, and blood was sampled from the abdominal aorta. The area under frusemide plasma concentrations‐time curve (AUC0‐∞) was calculated and frusemide extraction by an organ was estimated from the ratio (AUCdist‐AUCprox)/AUCdist. The small intestine extracted 83% of the absorbed dose of frusemide but the first‐pass uptake by the liver and lungs was negligible. To assess the contribution of the intestine and the kidneys to the systemic clearance of frusemide, it was injected into the jugular vein and blood was sampled proximal and distal to each organ. The kidneys extracted 24% of frusemide circulating in the renal arteries; on the other hand, the ability of the intestine to extract frusemide from the systemic circulation could not be detected. The lungs did not metabolize frusemide in vitro; the rate of metabolism of frusemide in vitro by kidneys was similar to that estimated in the intestine, and both rates were faster (P<0.05) than that observed in the liver. It is concluded that in rabbits, presystemic metabolism of frusemide is carried out by the intestine, and that systemic clearance of frusemide is mainly performed by the kidneys, although other organs, such as the intestine and the liver, must contribute to it.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.