Laboratory studies of 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate (SaH 42-348)— A new hypolipidemic agent

Timms, A. R.; Kelly, Lawrence A.; Ho, Robert S.; Trapold, J. H.

doi:10.1016/0006-2952(69)90281-0

Cited by 28 publications

(5 citation statements)

References 10 publications

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“…The proliferation of SER by these drugs may have been independent of the peroxisome proliferation and related to the induction of drug-metabolizing enzymes, as proposed for the compounds (such as phenobarbital [6]) which induce solely the SER. Slight increases in cytochrome P-450, metabolism of testosterone, and N-demethylase activity have been reported in rats treated with Sail 42-348 and clofibrate, suggesting induction of microsomal enzymes (40,45). However, the increases were not as marked as those seen in animals treated with phenobarbital.…”

Section: Peroxisome-associated Enzymesmentioning

confidence: 97%

Morphometric analysis of the ultrastructural changes in rat liver induced by the peroxisome proliferator SaH 42-348.

Moody¹,

Reddy²

1976

The Journal of Cell Biology

127

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The changes occurring in hepatocytes of F-344 male rats during a 3-wk treatment with a hypolipidemic agent, 1-methyl-4-piperidyl-b/s[p-chlorophenoxy]acetate (Sail 42-348), have been evaluated by morphometric and biochemical methods. The twofold increase in liver weight resulted from a significant increase in hepatocyte cytoplasm as well as a moderate increase in the number of liver cells. The peroxisome population and SER played an overwhelming part in the hypertrophy of hepatocytic cytoplasm. The relative volume and the surface density of peroxisomes increased ninefold and sevenfold, respectively. The increase in the collective peroxisome volume resulted from an increase in both the number and the average volume of peroxisomes. The SER also demonstrated a substantial increase in these values. The relative volume and surface density of mitochondria were not significantly altered in comparison to controls, while these values for RER decreased onefold. Studies on the lobular distribution of cytoplasmic organeUes before and during treatment revealed that the relative volume and surface density of peroxisomes and SER increased from periportal to centrilobular cells of the hepatic lobule, whereas mitochondrial values decreased from periportal to centrilobular cells. The RER values were fairly constant in different parts of the hepatic lobule. The increase in peroxisome and SER volume and surface area was first evident within the first 3 days of Sail 42-348 treatment and these values continued to increase, reaching a steady state within 2 wk. The time course of increase in catalase and carnitine acetyltransferase activities correlated with the morphometric data on the peroxisomes. After cessation of Sail 42-348 treatment, the peroxisome values decreased rapidly within the first 3 days and reached control levels within 1 wk. Moderate reduction in SER values occurred after withdrawal of the drug, but these values remained higher than controls even after 2 wk, suggesting that the reduction in the amount of circulating peroxisome proteins may result in empty SER channels. On the 4th day of drug withdrawal a significant increase in the relative volume and surface density of lysosomes was

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Section: Peroxisome-associated Enzymesmentioning

confidence: 97%

Morphometric analysis of the ultrastructural changes in rat liver induced by the peroxisome proliferator SaH 42-348.

Moody¹,

Reddy²

1976

The Journal of Cell Biology

127

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“…4) Table 1). For example, SaH42-348 has been reported to be 8-9 times more effective than CPIB in decreasing serum lipids (9,10) whereas S-8527 (15)(16)(17)(18) and WY-14643 (12,38), particularly at low drug concentrations, were up to 180 times more effective than CPIB.…”

Section: Resultsmentioning

confidence: 99%

Hypolipidemic drugs are inhibitors of phosphatidylcholine synthesis.

Parthasarathy¹,

Kritchevsky²,

Baumann³

1982

Proc. Natl. Acad. Sci. U.S.A.

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“…Lifibrate (1-Methyl-4-piperidinyl bis (4-chloro-phenoxy) acetate), also named SAH 42-348, is an inhibitor of cholinephosphotransferase (CPT), which is applied for the clinical treatment of hyperlipidemia with promising outputs [ 19 ]. However, the potential role of Lifibrate in treating IS remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

Lifibrate attenuates blood-brain barrier damage following ischemic stroke via the MLCK/p-MLC/ZO-1 axis

Duan,

Deng,

Tang

et al. 2024

Aging

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Dysfunction of tight junction proteins-associated damage to the blood-brain barrier (BBB) plays an important role in the pathogenesis of ischemic stroke. Lifibrate, an inhibitor of cholinephosphotransferase (CPT), has been used as an agent for serum lipid lowering. However, the protective effects of Lifibrate in ischemic stroke and the underlying mechanism have not been clearly elucidated. Here, we employed an in vivo mice model of MCAO and an OGD/R model in vitro . In the mice models, neurological deficit scores and infarct volume were assessed. Evans Blue solution was used to detect the BBB permeability. The TEER was examined to determine brain endothelial monolayer permeability. Here, we found that Lifibrate improved neurological dysfunction in stroke. Additionally, increased BBB permeability during stroke was significantly ameliorated by Lifibrate. Correspondingly, the reduced expression of the tight junction protein ZO-1 was restored by Lifibrate at both the mRNA and protein levels. Using an in vitro model, we found that Lifibrate ameliorated OGD/R-induced injury in human bEnd.3 brain microvascular endothelial cells by increasing cell viability but reducing the release of LDH. Importantly, Lifibrate suppressed the increase in endothelial monolayer permeability and the reduction in TEER induced by OGD/R via the rescue of ZO-1 expression. Mechanistically, Lifibrate blocked activation of the MLCK/ p-MLC signaling pathway in OGD/R-stimulated bEnd.3 cells. In contrast, overexpression of MLCK abolished the protective effects of Lifibrate in endothelial monolayer permeability, TEER, as well as the expression of ZO-1. Our results provide a basis for further investigation into the neuroprotective mechanism of Lifibrate during stroke.

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Laboratory studies of 1-methyl-4-piperidyl bis(p-chlorophenoxy) acetate (SaH 42-348)— A new hypolipidemic agent

Cited by 28 publications

References 10 publications

Morphometric analysis of the ultrastructural changes in rat liver induced by the peroxisome proliferator SaH 42-348.

Morphometric analysis of the ultrastructural changes in rat liver induced by the peroxisome proliferator SaH 42-348.

Hypolipidemic drugs are inhibitors of phosphatidylcholine synthesis.

Lifibrate attenuates blood-brain barrier damage following ischemic stroke via the MLCK/p-MLC/ZO-1 axis

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