2,3,7,8‐tetrachlorodibenzo‐p‐dioxin induced alterations of pyruvate carboxylase levels and lactate dehydrogenase isozyme shifts in C57BL/6J male mice

Abstract

A dose-dependent reduction of hepatic pyruvate carboxylase levels and activity occurs in C57BL/6J male mice given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) i.p. in a corn oil carrier. The dose range was from 1 to 75 micrograms/kg body weight and the analysis was done 8 days postinjection. At the maximum TCDD level investigated, we found a 10-fold reduction in pyruvate carboxylase activity. Furthermore, TCDD at a dose of 1 microgram/kg body weight blocks corn oil induction of an increase in the amount of pyruvate carboxylase in liver protein extracts. At doses beyond those required to initiate a reduction in pyruvate carboxylase, lactate dehydrogenase isozyme patterns shift. This is accompanied by an increase in blood lactic acid levels. We propose that TCDD-mediated reduction in pyruvate carboxylase and lactate dehydrogenase isozyme shifts may represent a major component in TCDD toxicity.

Expression of hepatic pyruvate carboxylase mRNA in C57BL/6J Ahb/b and congenic Ahd/d mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…At 50 and 75 mg/kg TCDD dose, the response of Ahb/b mice are, respectively, 3-and 10-fold greater than that seen in the Ahd/d mice. The reduction in PC mRNA levels is associated with a coincidental reduction, previously reported, PC level and enzyme activity (11). These results suggest that the effect of TCDD on PC in mouse liver is at the transcriptional level.…”

“…Based on the observation that elevated plasma levels of corticosteroids have been reported in TCDD-treated animals (34), one would expect PC to be up regulated in TCDD-treated animals. To the contrary, our data indicates that the PC activity level and mRNA in liver is down regulated (11). TCDD appears to cause the PC gene to become nonresponsive to its normal physiological stimuli.…”

“…They report reduced activities for key enzymes necessary for glucose anabolism, namely, pyruvate carboxylase (PC, EC 6.4.1.1) and phosphoenol pyruvate carboxykinase (PEPCK, EC 4.1.1.3.2) (10). In a previous study, we reported a dose-dependent reduction of hepatic PC levels and activity in C57BL/6J (Ahb'/") mice exposed to various amounts of TCDD (11). Mechanistic studies reveal that TCDD acts via the aromatic hydrocarbon receptor (AhR), which is a ligand-dependent transcription factor (12).…”

Ah receptor involvement in mediation of pyruvate carboxylase levels and activity in mice given 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin

“…Lactate dehydrogenase (LDH) isozyme and plasma lactate level did not change over the dose range investigated. Previously reported corn oil-induced increases in level and activity of PC in Ahbb mice were not observed in AhdId mice used in this study (6).…”

“…= -1.0 pg/kg body weight) (6). TO confirm that changes in PC activity with respect to TCDD dose are accompanied by a reduction in PC mass, western blot analysis for PC in Ahbjb and Ahd'd mice was carried out.…”