Chem. Res. Toxicol. 1996, 8, 77-81
77
Effect of the Peroxisome Proliferator Perfluoro-n-decanoicAcid on Glucose Transport in the Isolated Perfused Rat Liver Carol M. Goecke-Flora,? John F. Wyman,f Bruce M. Jarnot,+?*>$ and Nicholas V. Reo*>+ Department of Biochemistry and Molecular Biology, Department of Physics IKetteringScott Magnetic Resonance Laboratory, Wright State University and Kettering Medical Center, Dayton, Ohio 45429, and Tri-Service Toxicology Laboratory, Wright Patterson Air Force Base, Ohio 45433 Received July 29, 1994@
The perfluorinated carboxylic acid, perfluoro-n-decanoic acid (PFDA), is a known peroxisome proliferator which displays toxicity in rodents. Using a paired-tracer first-pass extraction technique, the effect of PFDA on hepatic glucose transport was determined in the isolated perfused rat liver. I n brief, livers isolated from PFDA-treated and control rats on day 5 posttreatment were administered the radiolabeled glucose analog, 3-O-[14Clmethyl-~-glucose ([14C13-O-MG)in addition to ~~uctose-l-~H(N)lsucrose ([3Hlsucrose), which served as a measure of extracellular volume. Hepatic glucose transport was calculated from the change in the ratio [14C13-0-MG/13Hlsucroseduring passage through the liver. Data from this study indicate that PFDA inhibits hepatic glucose transport. Percent hepatic glucose extraction is 1.8-fold greater in controls than in PFDA-treated rats. No significant difference in lactate dehydrogenase levels was observed in the liver perfusate from PFDA-treated and control rats. This suggests that the difference in percent glucose extraction between PFDA-treated and control groups is specifically due to the PFDA treatment and is not attributed to differences in liver viability between groups. Although the exact mechanism for this inhibition in hepatic glucose transport is not known, it is hypothesized that PFDA may have a major impact on membrane structure/ function which, in turn, may alter glucose transport.
Introduction Perfluoro-n-decanoic acid (PFDA)’ is a perfluorinated carboxylic acid and a known peroxisome proliferator. Others have shown that a single intraperitoneal (ip) injection of PFDA in rats results in a characteristic “wasting syndrome” and delayed lethal toxicity (1, 2). Toxic symptoms include pronounced hepatomegaly, due to both hyperplasia and hypertrophy, pronounced hypophagia, and marked body weight loss. Hepatic studies reveal elevated triglycerides (3),changes in the ratio of saturated to unsaturated fatty acids ( I , 21, decreased ketogenesis (4),2proliferation of peroxisomes and smooth endoplasmic reticulum (5, 6), mitochondrial disruption (71, decreased mitochondrial and peroxisomal P-oxidation (3,8-10),2 induction of cytochrome P450-4A1 (11),and increased w-oxidase a ~ t i v i t y .At ~ present, the toxicological mechanism associated with PFDA treatment and the significance of the increase in liver peroxisomes are not understood.
* Correspondence and requests for reprints should be addressed to this author at KSMRL, Cox Institute, Wright State University, 3525 Southern Blvd., Dayton, OH 45429. Phone: (513) 297-8046; Fax: (513) 294-7412; E-Mail:
[email protected]. + Wright State University and Kettering Medical Center. *WrightPatterson Air Force Base. 8 Present address: Exxon Biomedical Sciences, Inc., Mettlers Rd., CN2350, East Millstone, NJ 08875-2350. Abstract published in Advance ACS Abstracts, November 15,1994. Abbreviations: PFDA, perfluoro-n-decanoic acid; G6P, glucose 6-phosphate; GK, glucokinase; 2-DG, 2-deoxy-~-glucose;2-DG6P, 2-deoxy-D-glucose 6-phosphate; LDH, lactate dehydrogenase; [l4C130-MG, 3-O-[14C]methyl-~-glucose;[3Hlsucrose, [fructo~e-l-~H(N)]sucrose; GLUT 2, hepatic glucose transporter; 9% E, percent hepatic extraction. G. D. Pilcher, unpublished results. B. M. Jarnot, J. R. Okita, and W. J. Schmidt, unpublished results. @
0893-228x/95/2708-0077$09.00/0
Recently, we used 13C NMR spectroscopy to investigate the effects of PFDA on hepatic gluconeogenesis and glycogenesis in rats in vivo (12). The data show that PFDA inhibits hepatic glucose and alanine utilization. Also, PFDA completely inhibits glycogenesis from glucose while glycogen synthesis from alanine remains functional. The fact that the glycogenic pathways of glucose and alanine converge a t glucose 6-phosphate (G6P)and proceed via a common pathway to glycogen indicates that the glycogenic pathway from G6P to glycogen remains functional in PFDA-treated rats. This suggests that PFDA may inhibit either the hepatocellular transport of glucose and/or its phosphorylation by glucokinase (GK). Data from the same study also show that, following the administration of an intravenous bolus of the glucose analog 2-deoxy-~-glucose(2-DG),PFDA-treated rats have lower levels of hepatic 2-deoxy-~-glucose6-phosphate (2DG6P) than controls (12). Like glucose, 2-DG is transported into hepatocytes via the glucose transporter and is phosphorylated by GK to form 2-DG6P; however, 2-DG6P is not a substrate for glycolysis nor glycogenesis (13,141. The fact that PFDA-treated rats show significantly less 2-DG6P than corresponding controls is consistent with the hypothesis that PFDA inhibits either the transport of 2-DG into the hepatocyte andor its phosphorylation by GK. The goal of this study was to determine the effect of PFDA on hepatic glucose transport. This was accomplished using a paired-tracer first-pass extraction technique (15-1 7) in isolated perfused rat livers. In general, data from this study indicate that PFDA inhibits hepatic glucose transport.
0 1995 American Chemical Society
Goecke-Flora et al.
78 Chem. Res. Toxicol., Vol. 8, No. 1, 1995
Materials and Methods Materials. Ultrapure (99+%) PFDA [CF3(CF2)&02Hl was obtained from Technolube Products Co. (Los h g e l e s , CAI. Radiolabeled compounds, 3-0-[14C]methyl-D-glucose (38.3 pCi/ pmol; 0.1 mCi/mL) and Ifruct~se-l-~H(N)lsucrose (1mCi/mL), were purchased from Sigma (St. Louis, MO). Liver perfusion studies utilized Kreb's improved Ringers I solution which was prepared in house with the following composition (mM): NaCl (119.01, KCl(4.71, CaCl2 (3.41, KHzPO4 (1.21, MgSO4-7HzO (2.41, NaHC03 (25.0), D-glucose (11.5), and sucrose (2.0). The buffer was gassed with 95% 02/5%COz for 30 min, pH = 7.4. Animals. Male Fischer-344 rats (200-310 g) were obtained from Harlan (St. Louis, MO). The animal housing area was maintained at 22 "C with a 12 h lighudark cycle. Rodents were fed Purina Mills rodent lab diet 5008. PFDA-treated rats (n= 7) received a single ip injection of 50 m g k g PFDA dissolved in 1:1 (viv) propylene glycollwater (vehicle). Corresponding control animals (n = 8) received a single ip injection of vehicle. Stock solutions were prepared such that the ip volume did not exceed 0.5 mL. Previous studies from our laboratory indicate t h a t this volume of vehicle solution causes no distress or peritoneal reaction. Following exposure to PFDA, animals were individually housed in metabolism cages. Body weights and food consumption were monitored daily, and control animals were given the same amount of food that their paired partners had consumed on the previous day (pair-feeding). Pair-feeding simulates the hypophagic effects associated with PFDA treatment. All animals were fasted 16-24 h prior to experiments. Perfused Liver. At 5 days posttreatment, rats were anesthetized with halothane (5% for inductiodl% maintenance) and livers were surgically isolated a s described by Hems et al.(18). In general, livers were exposed by a xiphoid-pubis midline incision. Intestines were gently placed to the animal's left in moist gauze, and the bile duct was cannulated (PE 10). Caudate lobes were freed by tying two ligatures around the esophagus and incising between the ligatures. The portal vein was cannulated (Bard-A-Cath, 16 gauge), and livers were initially perfused with 0.8 mL of a heparinized saline solution (500 units of heparirdml of 0.9% NaC1) followed by perfusion with warm, oxygenated Kreb's improved Ringers I solution (hemoglobin-free) at 10 m u m i n . The thorax was opened to expose the heart, and the inferior vena cava was cannulated (PE 240-1.7 mm i.d.1 via an incision in the right atrium. Livers were excised, washed with warm saline, transferred t o the perfusion cabinet (maintained at 37 "C), and connected into the perfusion circuit. Livers were placed into a Petri dish lined with a silk cloth; cannulae positions were optimized for unobstructed flow; and the perfusion flow rate was increased to 25 m u m i n . Livers were perfused in a n anterograde direction using a recirculating system for a stabilization period of 30 min. During this time, hepatic pressure, effluent perfusion rate, and bile flow were monitored. In addition, perfusate samples (1.0 mL) were obtained a t 0, 10, 20, and 30 min for lactate dehydrogenase (LDH) determinations. These samples were stored on ice until analyzed (no longer than 6 h). LDH determinations were performed on a Kodak Ektachem Model 700 XR (Rochester,Mn. Perfusion Apparatus. A diagram of the perfusion apparatus is shown in Figure 1. This apparatus employed two reservoirs (nonradioactive vessel 1 and radioactive vessel 21, each containing 100 mL of Kreb's Ringer solution. The radioactive reservoir (vessel 2) also contained 0.25 pCi each of 3-0[14C]methyl-D-glucose ([l4C13-0-MG) and [fr~ctose-l-~H(N)]sucrose ([3H]sucrose). Similar to D-glucose, [l4C13-0-MGequilibrates rapidly between the intracellular and extracellular spaces, but unlike glucose, this analog is not metabolized (19, 20). Others have shown t h a t the affinity of D-glucose and 3-0MG for the hepatic glucose transporter (GLUT 2) is approximately equal (21, 22). In the isolated perfused liver, [3H]sucrose does not penetrate the cell and, therefore, diffises only into the extracellular space (23). Sucrose thus served as a measure of extracellular volume. Hepatic glucose transport was calculated from the change in the ratio [14C13-0-MG/[3Hlsucrose during passage through the liver.
Bubble trap
7
Sample
35 % 02
5% C02
Hepat
W
Membrane Oxygenator
Figure 1. A diagram of the perfusion apparatus. Perfusion from vessel 1 (nonradioactive vessel) used a recirculating system. Perfusate flowed through a membrane oxygenator (12 feet of Silastic tubing gassed with 95% 02/5% COz), temperature probe, filter, bubble trap, pH probe, and pressure gauge before reaching the liver. The effluent perfusate then passed through a pressure gauge and was collected back into the original vessel. Perfusate from vessel 2 (radioactive vessel) was used in a nonrecirculating manner with effluent collected directly into scintillation vials as described in the Materials and Methods. Perfusion from the nonradioactive reservoir (vessel 1)used a recirculating system. Following a 30 min stabilization period, perfusion of the tissue with the radiolabeled isotopes was initiated. Flow of the radioactive perfusate contained in vessel 2 was controlled with a stopcock, and perfusion from this reservoir was non-recirculating. Tissue effluent samples were collected manually into scintillation vials at 2 s intervals for approximately 2 min. Following collection of the last effluent sample, the influent tubing was disconnected from the portal vein catheter and a sample of the influent fluid was collected. At the end of the experiment, livers were blotted dry and weighed. Animal Criteria. To ensure maximum and similar tissue viability between PFDA-treated and control livers, the following set of criteria was established based on values obtained from pair-fed control animals: (i) successful surgery with no apparent problems, (ii)initial influent hepatic pressure 540 mmHg, and (iii) final hepatic LDH release 520 u n i t d g h ) . Livers failing to meet any of the above criteria were not included in the data analyses. Analytical Methods. Influent and effluent samples were prepared for liquid scintillation analysis by adding 10 mL of ScintiVerse BD scintillant (Fisher Scientific)to each sample and allowing time for temperature equilibration in the scintillation counter prior to data acquisition. The 14C and 3H activities in each sample were counted using a Packard TriCarb 4530 liquid scintillation analyzer with external standardization. All samples were counted initially for 2 min (preliminary data) in order to select the effluent samples which show the first appearance of measurable amounts of [3H]sucrose. A measurable amount of [3H]sucrose was defined as disintegrations at least 3-fold greater than background. These selected samples, in addition to the influent sample, were analyzed twice for 10 min, and duplicate disintegrations were averaged. Percent hepatic extraction (% E ) of ['*C13-0-MG relative to the extracellular reference, L3H1-
Chem. Res. Toxicol., Vol. 8, No. 1, 1995 79
Effect of PFDA on Hepatic Glucose Transport
Table 1. Percent Hepatic Glucose Extraction ( % E ) Dataa dpmb treatment control
sample influent
3H
14c
6262.98
6760.73
167.55 304.20 564.93
123.85 207.08 330.97
5421.17
6756.41
170.03 282.11 462.32
171.61 298.53 469.90
effluent 1 effluent 2 effluent 3 PFDA
influent effluent 1 effluent 2 effluent 3
%Ed
dpm ratioC Rout Rin
sample
% Ee (mean =k SE)
av
1.08 0.74 0.68 0.59
27.14 f 3.57 (n = 8)
31.48 45.37 1.25
1.01 1.06 1.01
15.48 f 2.23 (n = 7)
19.20 19.20
Representative set of data from a PFDA-treated and a control rat which was used to determine % E . Table also includes % E (mean dpm values for 3H and 14Cfrom influent and selected effluent samples for a n individual rat from each treatment group. Data shown are the average of 10 min duplicate 14Cand 3H dpm. Ratio of isotope activities in the influent (Ri, = 14Ci,,PHin)and effluent samples (Rout= 14CouJ3Hout).Percent glucose extraction calculated for each selected effluent sample for the representative data shown. These values were “averaged” to yield the % E for each animal. e Percent glucose extraction (mean f SE) determined from the “average” % E calculated for each rat in PFDA-treated and control groups. Data are significantly different (p = 0.02). & SE) for PFDA-treated and control groups.
sucrose, was derived from the ratios of the isotope activities in the influent (Rin= 14Cin/3Hin) and effluent samples (Rout= 14C0uJ 3Hout) as follows:
% E = 100 x [l - (Rou&n)l Data for the first 3 samples (6 s after appearance of measurable amounts of [3H]sucrose) were used to calculate 3 separate values of percent hepatic glucose extraction for each animal. These 3 early samples were then averaged to give the closest estimation of maximal glucose uptake due to unidirectional influx of glucose into hepatocytes (15,17). A representative set of data from a PFDA-treated and a control rat is shown in Table 1. Mean values of % E were calculated for both PFDA-treated and control groups. Statistical Analyses. Statistical analyses of data employed Student’s t-test for unpaired data. Data were considered statistically significant at a value o f p 5 0.05. Error estimates are given a s the standard error of the mean (SEX
Results Hepatic tissue viability was based on surgery success, hepatic pressure, and hepatic LDH release levels as described in Materials and Methods. Influent hepatic pressures for PFDA-treated and control rats (mean f SE) were 23 f 3 and 23 f 2 mmHg, respectively. Hepatic LDH release values for PFDA-treated and control rats (mean f SE) at the 30 min time point were 10 f 2 and 11 f 1 units/(gh). Eight of 13 control animals and 7 of 15 PFDA-treated animals met these criteria. Figure 2 shows a representative plot of the preliminary effluent [3Hlsucrose and [14C]3-0-MGdisintegrations (2 min time average) obtained from a PFDA-treated rat. When plotted on a scale to display all data points (as shown), differences between PFDA-treated and control animals are not apparent. Thus, all animals yield plots that appear similar when displayed a t this scale. For this reason a plot of a control animal is not shown. In Figure 2, base-line 3H and 14C disintegrations are observed from approximately 0 to 20 s, followed by a steady increase in disintegrations attributable to both 14Cand 3H as the substrates appear in the liver effluent. After 60 s, 14Cand 3H disintegrations begin to plateau. At the plateau, the level of dpm for 14Cis greater than 3H due to the fact that the level of dpm for 14C is greater than 3H in the perfusate reservoir. Percent hepatic glucose extraction was calculated from the first three samples showing the first appearance of measurable amounts of [3H]sucrose (described in Materials and Methods). The
7000
a b
6000
*
5000.
n
Y
4000.
‘F 5
3
3000-
t
e
0
P
2000:
0’ e
-
0
0.
:-------Gn
1000
o
20
40
60
ao
100
Time (s) Figure 2. A representative plot of the preliminary (2 min time average) effluent [3H]sucrose (closed circles) and [l4C13-0-MG (open circles) disintegrations obtained from a PFDA-treated rat. Percent hepatic glucose extraction was calculated from the first three samples showing the first appearance of measurable amounts of [3Hlsucrose. The data points representing these selected samples are circled.
data points representing these selected samples are circled in Figure 2, and the significance of these points for the calculation of % E is explained in the Materials and Methods. Table 1 shows influent and effluent 14C and 3H dpm data obtained from a representative PFDAtreated rat and a control rat. In addition, Table 1shows the calculated Rin, Rout,and percent hepatic glucose extraction for each of these animals. Percent hepatic glucose extraction was determined for all PFDA-treated and control rats, and mean f SE values are given in the table. The data indicate that control rats yield a 1.8fold greater percent hepatic glucose extraction compared to PFDA-treated rats ( p = 0.02).
Discussion In this study, the effect of PFDA on hepatic glucose transport was assessed on day 5 posttreatment by measuring percent hepatic glucose extraction in pedused livers from PFDA-treated and control rats. This study demonstrates that PFDA significantly inhibits hepatic
80 Chem. Res. Toxicol., Vol. 8,No.1, 1995
glucose transport. These data are consistent with the results from a previous study which show that, following the administration of 2-DG, PFDA-treated rats yield a significantly lower level of hepatic 2-DG6P than control (12).In both studies, animal treatment protocols were identical. This decrease in 2-DG6P was believed to be attributed to either a n inhibition in glucose transport and/or GK activity. Data from the present study clearly show that an inhibition of glucose transport at least partially accounts for the observed decrease in hepatic 2-DG6P in PFDA-treated rats. An accurate quantitative assessment of the effect of PFDA on GK activity is not possible due to differences in experimental protocol between the 2-DG6P study and this glucose transport study &e., different glucose concentrations and whole animal model versus perfused liver model). Glucokinase activity is expected to be lower in PFDA-treated animals since less glucose is available for phosphorylation due to the inhibition in glucose transport. LDH is a cytoplasmic enzyme which serves as a n indicator of irreversible cell damage. Others have shown that the maximal LDH release in perfused livers from 24-h fasted rats is 20 f 4 units4g-h) (24,25). For this reason, only livers with a final hepatic LDH 520 units/ (gh) were considered viable. PFDA-treated and control rats show no significant difference in hepatic LDH release levels. This suggests that the difference in percent glucose extraction between PFDA-treated and control groups is specifically due to the PFDA treatment and is not attributed to differences in liver viability between groups. Using a similar technique, Ibu et al. have measured percent hepatic glucose extraction in ad libitum fed control rats to be ca. 49.6 f 1.6 (17);however, due to differences in the perfusion protocol and in the nutritional status between animals, a direct comparison between these data and our results is not appropriate. Other studies have shown a 60% decrease in liver glucose transporter GLUT 2 mRNA transcription upon starvation (26,271.This suggests that the percent glucose extraction may be lower in the animals used in our study than in fed control animals used by Ibu et al. due to nutritional differences. Several studies have shown that glucose transport activity is influenced by the nature of the cell membrane (28-30). Glucose is transported into the liver via the glucose transporter, GLUT 2, which is localized primarily in the plasma membrane (31).PFDA may indirectly alter hepatocellular glucose transport by changing membrane composition and fluidity. In fact, Bartles et al. have shown that short-term exposure of rodents to ciprofibrate, another peroxisome proliferator, leads to alterations in the expression and modification of several hepatocyte plasma membrane proteins (32).In addition, Serafini et al. have shown that treatment of rats with the peroxisome proliferator clofibrate causes a n increase in membrane fluidity (33).Other studies indicate that PFDA treatment results in major shifts in the relative percentages of hepatic fatty acids with increases in palmitic and oleic acids and decreases in stearic, arachidonic, and docosahexanoic acids (1,2). PFDA-treated rats also show decreased osmotic fragility in red blood cells (1). Using 13CNMR spectroscopy, we have shown that PFDA-treated rats display improved spectral resolution in the 13C liver spectra relative to control rats (12). This is believed to reflect an increase in either membrane fluidity, liver triglycerides, and/or free fatty acids, which
Goecke-Floraet al. have been reported by others (3,34). Using 31PNMR spectroscopy,we have also shown that PFDA-treated rats display a marked increase in the level of hepatic phosphocholine-a major intermediate of phosphatidylcholine metabolism (35).Since phosphatidylcholine is the major component of phospholipid membrane, the elevated level of phosphocholine observed in PFDA-treated rats provides additional support to the theory that PFDA may exert its toxicity by changing membrane composition and fluidity. In conclusion, these data indicate that PFDA inhibits hepatic glucose transport. Although the exact mechanism for this inhibition is not known, i t is hypothesized that PFDA may have a major impact on membrane structure/function which, in turn, alters glucose transport.
Acknowledgment. The authors would like to thank Charles Alva, Deralyn Lee, and Tim Moore for their technical assistance with the perfused liver setup. This work was supported by the Air Force Office of Scientific Research, Air Force Systems Command, USAF, under Grant or Cooperative Agreement AFOSR-90 0148. References (1) Olson, C. T., and Andersen, M. E. (1983) The acute toxicity of perfluorooctanoic and perfluorodecanoic acids in male rats and effects on tissue fatty acids. Toxicol. Appl. Pharmacol. 70,362372. (2) George, M. E., and Andersen, M. E. (1986) Toxic effects of nonadecafluoro-n-decanoicacid in rats. Toxicol.Appl. Phannacol. 86,169-180. (3) Van Rafelghem, M. J.; Vanden Heuvel, J. P., Menahan, L. A., and Peterson, R. E. (1988) Perfluorodecanoic acid and lipid metabolism in the rat. Lipids 23, 671-678. (4) Badr, M. Z.,and Thurman, R. G. (1986) Inhibition of hepatic ketogenesis by metabolites of plasticizers: Studies with 2-ethylhexanol and structurally similar compounds in the isolated perfused liver. The Toxicologist 6, Abstract 464. ( 5 ) Harrison, E. H., Lane, J. S., Luking, S., Van Rafelghem, M. J., and Andersen, M. E. (1988)Perfluoro-n-decanoicacid: Induction of peroxisomal B-oxidation by a fatty acid with a dioxin-like toxicity. Lipids 23, 115-119. (6) Intrasuksri, U., and Feller, D. R. (1991)Comparisonof the effects of selected monocarboxylic and perfluorinated fatty acids on peroxisome proliferation in primary culture rat hepatocytes. Bwchem. Pharmacol. 42, 184-188. (7) Van Rafelghem, M. J., Mattie, D. R., Bruner, R. H., and Andersen, M. E. (1987)Pathological and hepatic ultrastructural effects of a single dose of perfluoro-n-decanoic acid in the rat, hamster, mouse, and guinea pig. Fundam. Appl. Toxicol. 9, 522-540. (8)Vanden Heuvel, J. P., Kuslikis, B. I., Shrago, E., and Peterson, R. E. (1991) Inhibition of long-chain acyl-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes. Biochem. Pharmacol. 42, 295-302. (9) Singer, S. S., Andersen, M. E., and George, M. E. (1990)PerfluoroN-decanoic acid effects on enzymes of fatty acid metabolism. Toxicol. Lett. 54, 39-46. (10)Borges, T., Glauert, H. P., Chen, L. C., Chow, C. K , and Robertson, L. W. (1990) Effect of the peroxisome proliferator perfluorodecanoic acid on growth and lipid metabolism in Sprague Dawley rats fed three dietary levels of selenium. Arch. Toxicol. 64,26-30. (11) Moody, D. E., Gibson, G. G., Grant, D. F., Magdalou, J., and Sambasiva, R. (1992) Peroxisome proliferators, a unique set of drug-metabolizing enzyme inducers: Commentary on a symposium. Drug Metab. Dispos. 20, 779-791. (12) Goecke, C. M., Jarnot, B. M., and Reo, N. V. (1994) Effects of the peroxisome proliferator perfluoro-n-decanoic acid on hepatic gluconeogenesis and glycogenesis: A 13C NMR investigation. Chem. Res. Toxicol. 7,15-22. (13) Hawkins, J. M., Jones, W. E., Bonner, F. W., and Gibson, G. G. (1987) The effect of peroxisome proliferators on microsomal, peroxisomal,and mitochondrial enzyme activities in the liver and kidney. Drug Metab. Rev. 18, 441-515.
Effect of PFDA on Hepatic Glucose Transport (14) Jacobs, A. E. M., Oosterhof, A., and Veerkamp, J. H. (1990) 2-Deoxy-~-glucoseuptake in cultured human muscle cells. Biochim. Biophys. Acta 1061,230-236. (15) Hooper, R. H., and Short, A. H. (1977) The hepatocellular uptake of glucose, galactose and fructose in conscious sheep. J.Physiol. 264, 523-539. (16) Ibu, J. O., MacDonald, I. A., and Short, A. H. (1978) A technique for measuring first pass extraction in the rat perfused liver. Br. J . Pharmacol. 64,469P. (17) Ibu, J. O., and Short, A. H. (1986) Interactions between monosaccharides and disaccharides during uptake by the perfused liver of rat. Q.J . Exp. Physiol. 71,599-607. (18) Hems, R., Ross, B. D., Berry, M. N., and Krebs, H. A. (1966) Gluconeogenesis in the perfused liver. Biochem. J . 101,284292. (19) Hetenyi, G., Jr., Norwich, H., Studney, D. R., and Hall, J. D. (1969) The exchange of glucose across the liver cell membrane. Can.J . Physiol. Pharmacol. 47,361-367. (20) Jay, T. M., Dienel, G. A., Cruz, N. F., Mori, K., Nelson, T., and Sokoloff, L. (1990) Metabolic stability of 3-0-methyl-D-glucose in brain and other tissues. J. Neurochem. 66,989-1000. (21) Burant, C. F., and Bell, G. I. (1992) Mammalian facilitative glucose transporters: Evidence for similar substrate recognition sites in functionally monomeric proteins. Biochemisty 31, 10414-10420. (22) Baur, H., and Heldt, H. W. (1977) Transport of hexoses across the liver-cell membrane. Eur. J . Biochem. 74,397-403. (23) Williams, T. F., Exton, J. H., Park, C. R., and Regen, D. M. (1968) Stereospecific transport of glucose in the perfused rat liver. Am. J . Physiol. 215,1200-1209. (24) Keller, B. J., Yamanaka, H., and Thurman, R. G. (1992) Inhibition of mitochondrial respiration and oxygen-dependent hepatotoxicity by six structurally dissimilar peroxisomal proliferating agents. Toxicology 71,49-61. (25) Liu, Y., and Thurman, R. G. (1992) Potentiation of adriamycin toxicity by ethanol in perfused rat liver. J . Pharmacol. Exp. Ther. 263,651-666.
Chem. Res. Toxicol., Vol. 8, No. 1, 1995 81 (26) Tiedge, M., and Lenzen, S. (1991) Regulation of glucokinase and GLUT-2 glucose-transporter gene expression in pancreatic B-cells. Biochem. J. 279,899-901. (27) Thorens, B., Flier, J. S., Lodish, H. F., and Kahn, B. B. (1990) Differential regulation of two glucose transporters in rat liver by fasting and refeeding and by diabetes and insulin treatment. Diabetes 39, 712-719. (28) Carruthers, A., and Melchior, D. L. (1984) Human erythrocyte hexose transporter activity is governed by bilayer lipid composition in reconstituted vesicles. Biochemistry 23, 6901-6911. (29) Carruthers, A, and Melchior, D. L.(1986)How bilayer lipids affect membrane protein activity. Trend. Biochem. Sci. 11, 331-335. (301 Carruthers, A., and Melchior, D. L.(1988) Role of bilayer lipids in governing membrane transport processes. In Lipid Domains and the Relationship to Membrane Function (Aloia,R. C., Curtain, C. C., and Gordon, L.M., Eds.) pp 201-225, Alan R. Liss, New York. (31) Thorens, B., Lodish, H. F., and Brown, D. (1990) Differential localization of two glucose transporter isoforms in rat kidney. Am. J . Physiol. 269, C286-C294. (32) Bartles, J. R., Khuon, S., Lin, X., Zhang, L.,Reddy, J. R,Rao, M. S., Isoye, S. T., Nehme, C. L., and Fayos, B. E. (1990) Peroxisome proliferator-induced alterations in the expression and modification of rat hepatocyte plasma membrane proteins. Cancer Res. 50,669-676. (33) Serafini, B., Cimini, A,, Sette, M., and Sartori, C. (1993) slP NMR of liver peroxisome membranes from normal and clofibrate-treated rats. Annu. Rev. Pharmacol. Toxicol. 39, 479-489. (34) Davis, J. W., 11, Vanden Heuvel, J. P., and Peterson, R. E. (1991) Effects of perfluorodecanoic acid on de nouo fatty acid and cholesterol synthesis in the rat. Lzpids 26, 857-859. (35) Reo, N. V., Goecke, C. M., Narayanan, L.,and Jarnot, B. M. (1994) Effects of perfluoro-n-octanoic acid, perfluoro-n-decanoic acid, and clofibrate on hepatic phosphorus metabolism in rats and guinea pigs in uiuo. Toxicol. Appl. Pharmacol. 124,165-173.
Tx9400969
