|Abstract or Summary
- Polychlorinated biphenyls (PCBs) have been reported to cause
alterations in the metabolism of phospholipids and glycerides in animals
and humans. This project was undertaken in an attempt to determine
the mode of action of PCBs and their primary metabolites on
phospholipid and glyceride biosynthesis.
The activity of sn-glycerol-3 phosphate acyltransferase was
inhibited by PCBs in vitro. The inhibition was noncompetitive suggesting
a binding to a site other than the active site on the enzyme. The
inhibition of the activity of this enzyme was accompanied by a general
decline in the in vitro synthesis of phospholipids by microsomes,
mitochondria and cell-free homogenates. Glyceride synthesis by mitochondria
and cell-free homogenates decreased while it increased in
After in vivo treatment of rats with PCB for 30 days, the activity
of microsomal sn-glycerol-3 phosphate acyltransferase declined. The
decline in enzyme activity was accompanied by a decreased incorporation
of radioactivity into microsomal phospholipids and glycerides.
On the other hand, mitochondria and cell-free homogenates consistently
showed apparent increases in the incorporation of radioactivity into phospholipids and glycerides after the PCB treatment.
The purified isomer, 2,4,5,2',4',5'-hexachlorobiphenyl elicited
the same kind of response as the commercial PCB preparation. It
inhibited the activity of sn-glycerol-3 phosphate acyltransferase
which caused a decrease in the synthesis of phospholipids in vitro.
Glyceride synthesis again increased in microsomes but decreased in
the cell-free homogenate.
The in vitro activities of glycerol kinase and diglyceride acyltransferase
were not affected by PCB at concentrations as high as 1.5
mM. This concentration was more than three times that needed to
inhibit sn-glycerol-3 phosphate acyltransferase.
Microsomal phosphatidate phosphatase activity was not affected
during the initial stages of catalysis, but after prolonged incubation,
there was a small increase (22 percent) or decrease (18 percent) in
the activity under in vitro and in vivo conditions, respectively. The
slight increase in the activity of this enzyme under the in vitro
conditions was observed at 1.2 mM PCB which was more than two times
that at which sn-glycerol-3 phosphate acyltransferase is significantly
The activity of phosphorylcholine-glyceride transferase was
inhibited at 1.5 mM PCB in vitro but the inhibition was much less than
observed with sn-glycerol-3 phosphate acyltransferase.
Two primary metabolites of PCB, 4'-chloro-4-biphenylol and
2',3',4',5,5'-pentachloro-2-biphenylol elicited the same kind of
response as PCBs in vitro. Both compounds inhibited the activity of
sn-glycerol-3 phosphate acyltransferase, with large decreases in the
in vitro synthesis of phospholipids by microsomes, mitochondria, and cell-free homogenates. Glyceride synthesis by mitochondria and homogenates
also decreased, but increased in the microsomes. The pentachlorobiphenylol
was a more potent inhibitor of the activity of
sn-glycerol-3 phosphate acyltransferase than PCBs. The inhibition of
the enzyme by this compound was also noncompetitive. The 4'-chloro-4-
biphenylol did not affect the activity of microsomal phosphatidate
phosphatase, but the pentachlorobiphenylol slightly stimulated the
enzyme activity (25 percent). The latter observation might in part
account for the increased glyceride synthesis observed in the microsomes.
The overall results are consistent with the conclusion that PCBs
and their metabolites inhibit phospholipid and glyceride synthesis at
the site of the reaction catalyzed by sn-glycerol-3 phosphate acyltransferase.
A model is proposed in this project which accounts for
all the observed results and is consistent with the conclusion drawn.