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

Abstract

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:

Subchronic Hepatotoxicity Evaluation of 2,3,4,6-Tetrachlorophenol in Sprague Dawley Rats

“…However, after 13 weeks of exposure, the severity of hypertrophy was minimal in the 10 mg/kg/day rats, and the incidence was not statistically significantly different compared to the control rats. Hepatocyte hypertrophy is typically observed with enzyme induction; although Phornchirasilp et al [22] observed significant increases in microsomal protein and cytochrome P450 levels in Sprague-Dawley rats dosed with 4-chlorophenol, studies reporting TCP-induction of liver metabolizing enzymes were not found suggesting that other pathways may be involved in the hypertrophy response. The observed hepatocyte vacuolation in conjunction with hypertrophy (Table 5) may indicate perturbation of lipid metabolism, a common sequel to hepatic injury.…”

Enhanced Bioremediation of 4-Chlorophenol by Electrically Neutral Reactive Species Generated from Nonthermal Atmospheric-Pressure Plasma

“…Among them, 4-chlorophenol (4-CP) is highly toxic to living organisms owing to its teratogenic, carcinogenic, and mutagenic characteristics as well as its persistence in the aquatic environments. 6 − 10 Moreover, the environmental and bio-degradation of 4-CP is difficult owing to its low water solubility and vapor pressure characteristics. 11 The US Environmental Protection Agency 12 and the European Union 13 have labeled 4-CP as a “priority pollutant”; that is, its presence in aquatic environments requires constant monitoring and that a concentration of 0.5 mg/L is the upper permissible limit of this compound in public water supply.…”

“…Chloroaromatic compounds have numerous industrial applications, including petroleum refining and the production of pesticides, paints, plastics, resins, textiles, iron, solvents, pharmaceuticals, and wood-preserving chemicals. − The former are released into the environment as byproducts of the latter. Among them, 4-chlorophenol (4-CP) is highly toxic to living organisms owing to its teratogenic, carcinogenic, and mutagenic characteristics as well as its persistence in the aquatic environments. − Moreover, the environmental and bio-degradation of 4-CP is difficult owing to its low water solubility and vapor pressure characteristics . The US Environmental Protection Agency and the European Union have labeled 4-CP as a “priority pollutant”; that is, its presence in aquatic environments requires constant monitoring and that a concentration of 0.5 mg/L is the upper permissible limit of this compound in public water supply .…”