Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: I. Chow‐fed animals

O'Brien, M.; Patel, Suman; Mukhopadhyay, A.; Newman, Howard; Feller, Dennis R.; S, Kokrady; Witiak, Donald T.; Lanese, Richard R.; Rice, Julie

doi:10.1007/bf02534996

Cited by 10 publications

(1 citation statement)

References 29 publications

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“…The major cholesterol-bearing serum lipoprotein in rats is HDL and the observed decrease in serum cholesterol by CPIB may be directly related to a reduction in the cholesterol concentration of HDL (32,33). Thus, the diminution of serum cholesterol found in CPIB-treated rats was further investigated and the results on HDL-cholesterol levels are presented in Figure 6D.…”

Section: Measurement Of Serum Lipid and Lipid-lipoprotein Concentratimentioning

confidence: 97%

Pharmacologic Effects of 4-Chlorophenol in Rats: Comparison to Clofibrate

Phornchirasilp¹,

Patel²,

Hanson³

et al. 1989

Experimental Biology and Medicine

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4-Chlorophenol (4-CP) is an identified trace contaminant in commercial clofibrate ipreparations and the pharmacologic effects of 4-CP have not yet been widely establlished. We have examined the dose-dependent effects of oral 4-CP and clofibrate adminlistration on selected hepatic parameters and on serum glucose, cholesterol, and triglyckride concentrations in male rats. 4-CP treatment (0.00125-0.08 mmol/kg, twice a day) of rats for 2 weeks increased hepatic microsomal protein (20-30%) and cytochrome P-450 (20-190%) contents without changing liver/body weight ratios. Both 4-CP (0.0025 mmol/kg body wt, twice a day) and CPIB (0.4 mmol/kg body wt, twice a day) treatment to rats for 2 weeks caused significant elevations in microsomal cytochrome P-450 content and in the maximal activities of ethylmorphine, aminopyrine, and benrphetamine N-demethylase, but not in the activity of zoxarolamine 6-hydroxylase. With the same dose of 4-CP, time-dependent increases in hepatic microsomal protein, cytochrome P-450, and the activity of benzphetamine N-demethylase were observed for a 4-week period, and the induction of hepatic microsomal benrphetamine N-demethylase activity by 4-CP was associated with an increased enzyme synthesis. 4-CP treatment produced a marked morphologic change in liver cell ultrastructure, including a proliferation of mitochondria and endoplasmic reticulum at lower 4-CP doses. A clustering of intracellular organelles (mitochondria and endoplasmic reticulum) and a foamy cyto-plasm1 were seen at doses greater than 0.01 mmol/kg, twice a day for 2 weeks, and at 0.0025 mmol/kg, twice a day for >4 weeks. The effects of 4-CP and clofibrate on fasting blood iglucose and fasting serum lipid levels were also monitored throughout an 8-week period. Both 4-CP (0.005 mmol/kg body wt, twice a day) and clofibrate (0.2 mmol/kg body wt, twice a day) produced significant elevations in fasting serum glucose levels, but this dosage of 4-CP did not alter serum lipid and lipoprotein parameters, whereas clofibrate significantly reduced serum total cholesterol and high density lipoprotein cholesterol levels. These results lead us to conclude that 4-CP does not contribute to the antilipidemic effects of clofibrate. [P.S.E.B.M. 1989[P.S.E.B.M. , Vol 1911 oronary artery disease has been defined as one of the major causes of death among the human C population in industrial nations (I), and elevated cholesterol and low density lipoprotein (LDL)cholesterol concentrations are now accepted as significant risk factors for the development of this disease (2). Clofibrate [ethyl-2(4-chlorophenoxy)-2-propionic acid, p-chlorophenoxyisobutynic acid ethyl ester, CPIB] and ' Current address:

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Section: Measurement Of Serum Lipid and Lipid-lipoprotein Concentratimentioning

confidence: 97%

Pharmacologic Effects of 4-Chlorophenol in Rats: Comparison to Clofibrate

Phornchirasilp¹,

Patel²,

Hanson³

et al. 1989

Experimental Biology and Medicine

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Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: II. High sucrose‐fed animals

Mukhopadhyay

Patel

O'Brien

et al. 1983

Lipids

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The hypolipidemic properties of ethyl 6-chlorochroman-2-carboxylate (II), 6-phenylchroman-2-carboxylate (III) and 6-cyclohexylchroman-2-carboxylate (IV) were compared to clofibrate (I) in sucrose-fed fasted male Sprague-Dawley rats. All compounds were administered at doses of 0.2 and 0.4 mmol/kg, orally, twice daily for 7 consecutive days. In this model, II was a more effective hypocholesterolemic drug than clofibrate, whereas III and IV were inactive. Chlorochroman II, like clofibrate, decreased serum alpha-lipoprotein cholesterol and pre-beta-lipoprotein triglyceride concentrations and concomitantly increased serum beta-lipoprotein triglyceride concentrations. In clofibrate-treated rats, serum free cholesterol concentrations increased concurrent with a reduction in serum lecithin: cholesterol acyltransferase activity, but no such correlation was observed for II. Only II lowered liver cholesterol levels and increased liver triglyceride levels. No consistent inhibition of liver microsomal 3-hydroxy-3-methylglutaryl-CoA reductase activity was observed with these analogs. The observed changes in triglyceride and cholesterol concentrations among serum lipoproteins were of a greater magnitude after chlorochroman II and clofibrate administration to sucrose-fed rats than in our previous studies using chow-fed fasted rats. These data suggest that chloro-substitution at the 6-position of the phenylchroman ring is important for hypolipidemic activity of these cyclic clofibrate analogs.

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Serum lipoprotein and apoprotein concentrations in 4‐(4‐chlorophenyl)‐2‐hydroxytetronic acid and clofibrate‐treated cholesterol and cholic acid‐fed rats

Kamanna

Newman

Patel

et al. 1989

Lipids

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Influence of clofibrate and an aci-reductone, 4-(4-chlorophenyl)-2-hydroxytetronic acid (CHTA) on lipoproteins and apoproteins was studied in cholesterol- plus cholic acid-fed rats. CHTA (0.4 mmol/kg body wt, twice daily) significantly lowered serum total cholesterol and triglyceride concentrations at both 10 and 16 days, whereas clofibrate at the same dose did not alter serum cholesterol levels, but elevated serum triglyceride concentrations at 16 days. The abnormal cholesterol-rich very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL) and low density lipoproteins (LDL) produced by cholesterol plus cholic acid were significantly reduced in their cholesterol content by treatment with CHTA, a compound having an oxidation reduction potential. Conversely, clofibrate administration increased VLDL-cholesterol with concomitant decreases in IDL- and LDL-cholesterol concentrations. Administration of CHTA to cholesterol- plus cholic acid-fed rats significantly increased concentrations of VLDL and IDL, but had no effect on HDL protein. Both CHTA and clofibrate administration to cholesterol- plus cholic acid-fed rats significantly lowered IDL protein concentrations. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies of apoproteins revealed that clofibrate treatment significantly reduced apoC-III and C-II in VLDL, C-II in IDL, and apoA-IV and A-I in HDL. Rats treated with CHTA significantly raised apoC-II and C-III in HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

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Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: I. Chow‐fed animals

Cited by 10 publications

References 29 publications

Pharmacologic Effects of 4-Chlorophenol in Rats: Comparison to Clofibrate

Pharmacologic Effects of 4-Chlorophenol in Rats: Comparison to Clofibrate

Hypolipidemic effects of clofibrate and selected chroman analogs in fasted rats: II. High sucrose‐fed animals

Serum lipoprotein and apoprotein concentrations in 4‐(4‐chlorophenyl)‐2‐hydroxytetronic acid and clofibrate‐treated cholesterol and cholic acid‐fed rats

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