Palmitoyl-CoA oxidase

Di(2-ethylhexyl) phthalate (0, 0.5, 1, 2.5 or 5 g/kg per day) was administered to Fischer 344 rats by oral gavage from birth through lactation day 21 and the activity of several peroxisomal enzymes was determined in the livers, kidneys and brains of the females and their offspring (Cimini et al., 1994). No pups survived exposure to doses of 2.5 g/kg per day. Pup growth was impaired at the two lowest doses. In the liver, cyanide-insensitive palmitoyl-CoA oxidase activity showed similar increases in pups and adult females. 

Rat (Sprague- Dawley) 5 d 1x/d (GO) Hepatic 10 100 (increased liver weight and activity of palmitoyl CoA oxidase and carnitine acetyl transferase) Dostal et al. 1987a ... 

Rat 28 d (AIpk/AP) 1x/d (GO) Hepatic 1000 (increased palmitoyl-CoA oxidase activity decreased superoxide dismutase and glutathione peroxidase activities) Elliot and Elcombe 1987 ... 

Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to DEHP. Limited information on hepatic effects in humans exposed to DEHP is available from studies of dialysis patients and cultured human hepatocytes. In one individual there was an increased number of liver peroxisomes after 1 year, but not after 1 month of treatment (Ganning et al. 1984, 1987). A serious limitation of this observation is that repeat biopsies were not obtained from the same patient, so that an appropriately controlled analysis is not possible. Additionally, analysis of liver biopsies from patients receiving other kinds of hypolipidemic drugs has not yielded any evidence for peroxisomal proliferation (Doull et al. 1999). Recognizing some limitations of using primary hepatocytes in vitro because of their tendency to lose some metabolic capabilities (Reid 1990), in cultured human hepatocytes there were no changes in the activities of peroxisomal palmitoyl-CoA oxidase and/or carnitine acetyltransferase when... 

Comments PPARa activation is a summary of trans-activation data as well as response of markers such as ACO and CYP4A gene, along with protein and enzymatic activity, which are indicators of PPARa activation and are dependent on level of PPARa expression. The endpoint examined in these studies is indicated below. + indicates a strong response, (+) indicates a weak response, and - indicates no response. Spaces left blank indicate no data available. It should be noted that the table does not include PCO data from monkey species otho- than Cynomolgus monkeys other monkey data (which is almost universally negative) are summarized in Klaunig et al. (2003). PCO, palmitoyl-CoA oxidase. 

In vitro and in vivo data on Cynomolgus monkeys (Table 17.3) and other species of monkeys (i.e., marmoset and Rhesus) indicate that the key events in the PPARa activator MOA are relatively nonresponsive in monkeys. Palmitoyl-CoA oxidase activity was evaluated in monkeys after in vivo exposure to a variety of PPARa activators [e.g., bezafibrate, clofibrate, DEHP, mono-2-ethylhexyl phthalate (MEHP), fenofibrate, nafenopin, and LY171883], and changes were minimal or nonexistent relative to controls (Klaunig et al. 2003). Moreover, Cynomolgus monkeys exposed to DEHP, DINP, or clofibrate failed to exhibit an increase in cell proliferation (Doull et al. 1999 Pugh et al. 2000). Cynomolgus monkeys treated for two weeks with clinically relevant doses of the PPARa activators fenofibrate or ciproflbrate exhibited increases in the number of hepatic peroxisomes (Hoivik et al. 

Another inhalation study in mice and rats correlated light microscopic and ultrastructural liver effects with liver levels of cyanide-insensitive palmitoyl CoA oxidase, a marker for peroxisomal -oxidation (Odum et al. 1988). Animals were exposed to 200 ppm of tetrachloroethylene for 28 days or 400 ppm for 14,21, or 28 days. Centrilobular hepatocellular vacuolization was induced in mice by tetrachloroethylene exposure. Electron microscopy revealed that this effect corresponded to lipid accumulation. Centrilobular hepatocytes with cytoplasmic eosinophilia on light microscopy had marked proliferation of cytoplasmic peroxisomes at the ultrastructural level, and there was a significant increase in the marker enzyme. These changes occurred in mice at both doses and all exposures and were most pronounced in male mice. Exposed male rats in both dose groups and female rats exposed to 400 ppm developed centrilobular hepatocellular hypertrophy, which ultrastructurally consisted of proliferation of smooth endoplasmic reticulum. There was no increase in peroxisomes (Odum et al. 1988). 

In man, at the protein level, two oxidases were found. The first one is palmitoyl-CoA oxidase, the counterpart of the rat enzyme with regard to substrate spectrum and... 

Van Veldhoven P.P., Vanhove G, Asselberghs S., Eyssen H.J. Mannaerts G.P. (1992) J. Biol Chem. 267, 20065-20074. Substrate specificities of rat liver peroxisomal acyl-CoA oxidases Palmitoyl-CoA oxidase (inducible acyl-CoA oxidase), pristanoyl-CoA oxidase (non-inducible acyl-CoA oxidase) and trihydroxycoprostanoyl-CoA oxidase. 

Two other oxidase activities have been described in rat liver peroxisomes, one acting on glutaryl-CoA, the other on valproyl-CoA. The glutaryl-CoA oxidase activity, however, co-purifies with the inducible palmitoyl-CoA oxidase. The valproyl-CoA oxidase was claimed to differ from the above descrihed acyl-CoA oxidases, but in our hands this activity was recovered mainly in the cytosol (Casteels, M. Van Veldhoven P. P., unpublished data). 

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