Kupffer cell factor mediated depression of hepatic parenchymal cell cytochrome P-450

Peterson, Theresa C.; Renton, Kenneth W.

doi:10.1016/0006-2952(86)90114-0

Cited by 60 publications

(16 citation statements)

References 22 publications

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“…In¯ammatory diseases and individual proin¯ammatory cytokines can depress cytochrome (CYP) P450 isozyme [30,32,39,40]. While the mechanism of this suppression is not clearly known, formation of NO, which may inhibit CYP450, is a plausible explanation [41].…”

Section: Discussionmentioning

confidence: 99%

Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis

Mayo

Skeith

Russell

et al. 2000

Brit J Clinical Pharma

117

134

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Aims In¯ammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil. Methods Eight RA patients were age-and sex-matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin-6 (IL-6) and nitrite (NO 2 ± ) were measured in predose samples. Results IL-6 and NO 2 ± concentrations were signi®cantly increased in parallel with disease severity. Oral clearance of both S-and R-verapamil was signi®cantly decreased by RA. While the unbound fraction of S-and R-verapamil decreased by 5 and 7-fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S-verapamil. AUC of norverapamil enantiomers was increased 2±3-fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR-interval was signi®cantly reduced by one fold and the effect on the heart rate and blood pressure did not increase. Conclusions RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood¯ow. A signi®cant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro-in¯ammatory cytokines and/or NO.

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Section: Discussionmentioning

confidence: 99%

Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis

Mayo

Skeith

Russell

et al. 2000

Brit J Clinical Pharma

117

134

View full text Add to dashboard Cite

show abstract

“…INTRODUCTION [9] in both ways depending on the activity of cransforming growth factors (TGF) typea respectively, of hepatocytc proporrant for the regulation of normal and pathologic liferation and are thought co play central roles in the liver function [1,2], As examples, Kupffer cell secreregulation of liver cell regeneration [ 13). In the present rions affect protein synthesis [3], influence protein study WC present evidence that Kupffer cells have the phosphorylation [4] and depress cytochrome P450 potency to stimulate and inhibit hepacocyte DNA synfunctions in parenchymal liver cells [5]. Kupffcr cells thesis in vitro determined by the ratio of active TGF@ to have been implicated also in the regulation of TGFcY.…”

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confidence: 88%

Bidirectional effects of Kupffer cells on hepatocyte proliferation in vitro

1991

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“…Kupffer cells are activated due to phagocytosis of the cellular debris resulting from cellular necrosis in liver disease (4 (12). In this paper, our results show that the media from monocyte cultures of patients with liver disease significantly decreased hepatocyte AHH activity compared to controls.…”

Section: Discussionmentioning

confidence: 53%

Depression of peripheral blood monocyte aryl hydrocarbon hydroxylase activity in patients with liver disease: Possible involvement of macrophage factors

Peterson

Williams

1987

Hepatology

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Aryl hydrocarbon hydroxylase activity was detectable in cultured macrophage monolayers of peripheral blood monocyte origin. Peripheral blood monocytes were isolated from patients with biopsy-confirmed liver disease and healthy volunteers. Macrophage monolayers were prepared and incubated at 37 degrees C. After 24 hr, the aryl hydrocarbon hydroxylase activity and cellular protein concentration were assayed on cell homogenates. The monocyte aryl hydrocarbon hydroxylase activity in cultured macrophages from normal volunteers was 1.23 +/- 0.16 (n = 19). The aryl hydrocarbon hydroxylase activity in macrophage cultures from patients with biopsy-confirmed liver disease was 0.48 +/- 0.05 (n = 20). This represents a significant (61%) decrease in monocyte aryl hydrocarbon hydroxylase compared to controls. The 20 patients have established cirrhosis or early stage liver disease. The established cirrhosis group includes alpha 1-antitrypsin deficiency-associated cirrhosis; primary biliary cirrhosis; alcoholic (Laennec's) cirrhosis; cryptogenic cirrhosis, and hemochromatosis. Early stage liver disease is attributed to methotrexate (Stage III), early stage primary biliary cirrhosis and alpha 1-antitrypsin deficiency. Our results indicate that the depression in monocyte aryl hydrocarbon hydroxylase activity is greater in patients with established cirrhosis than early stage liver disease. Our results further suggest that cultured monocytes from patients with liver disease spontaneously release soluble factors into the culture medium. Incubation of this medium, containing macrophage factors, with isolated hepatocytes significantly depress hepatocyte aryl hydrocarbon hydroxylase activity compared to medium obtained from cultures of monocytes from normal volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

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Kupffer cell factor mediated depression of hepatic parenchymal cell cytochrome P-450

Cited by 60 publications

References 22 publications

Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis

Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis

Bidirectional effects of Kupffer cells on hepatocyte proliferation in vitro

Depression of peripheral blood monocyte aryl hydrocarbon hydroxylase activity in patients with liver disease: Possible involvement of macrophage factors

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