Structure-Activity Relationships for Induction of Peroxisomal Enzyme Activities By Phthalate Monoesters in Primary Rat Hepatocyte Cultures

Abstract

Rat hepatocytes were cultured for 70 hours with a series of four isomeric octyl and five isomeric hexyl phthalate monoesters, and their effects on peroxisomal fatty acid beta-oxidation (palmitoyl-CoA oxidation) and carnitine acetyltransferase activities determined. All nine monoesters produced dose-related increases in enzyme activities and marked quantitative compound potency differences were observed. Generally octyl isomers were more potent than hexyl isomers and 2- and 3-ethyl substituted isomers were more potent than their straight chain and 1-ethyl substituted analogs. For example, mono(2-ethylhexyl)phthalate was more potent than mono(1-ethylhexyl)phthalate, and this was also observed after oral administration of the two isomers to rats for seven days. The cell culture data for induction of palmitoyl-CoA oxidation were used to generate quantitative structure-activity relationships. Relatively poor correlations were observed between biological activity and simple hydrophobic parameters, but a good correlation was obtained when compound electronic structural parameters, obtained by molecular orbital calculations, were employed. These studies demonstrate relationships between biological activity and chemical structure for a series of phthalate monoesters and indicate the potential usefulness of primary rat hepatocyte cultures to screen compounds for peroxisome proliferation.

Role of PPARα in mediating the effects of phthalates and metabolites in the liver

“…Additionally, branchchained esters in general were more potent in inducing peroxisome proliferation and enzyme induction than straight-chain phthalates in rat liver (DeAngelo et al, 1986;Barber et al, 1987). These potency differences have also been observed in vitro in hepatocyte cell culture when comparing the proximate monoester phthalate metabolites (Gray et al, 1982;Lake et al, 1987). However, the observed differences in phthalate ester effects were dose-dependent and most of the phthalate esters elicited some response, suggesting that they might all work through a common mechanism.…”

Airway inflammation and adjuvant effect after repeated airborne exposures to di-(2-ethylhexyl)phthalate and ovalbumin in BALB/c mice

“…PPAR␣ activation causes liver enlargement in rodents (Lake et al, 1987), which may serve as an indicator of systemic PPAR␣ effects. PPAR␣ and -␥ agonists may affect the immune system, showing both pro-and anti-inflammatory effects (Clark, 2002).…”

Comparative Effects of Phthalate Monoesters on Gap Junctional Intercellular Communication and Peroxisome Proliferation in Rodent and Primate Hepatocytes

“…However, the dose level used in those earlier studies was relatively low compared to the present study and is a likely explanation of the differences in results. Several reports also have shown that MNOP induces peroxisomal enzymes in vitro (Gray et al, 1983;Lake et al, 1986aLake et al, , 1986bLake et al, , 1987). In the current study, although the level of peroxisomal b -oxidation produced by MNOP was well above control in rat hepatocytes, large variability in the measurements may have masked the level of significance .…”

“…Because the monoesters are the active metabolites, they are commonly used for in vitro studies in preference to the parent phthalates. A number of phthalate monoesters have been studied in hepatocyte culture for various effects including elevated levels of peroxisomal b -oxidation as well as inhibition of gap junctional intercellular communication (Benford et al, 1986;Hasmall et al, 1999Hasmall et al, , 2000Klaunig et al, 1988;Lake et al, 1986aLake et al, , 1986bLake et al, , 1987.…”