Distribution of i.v. administered epidermal growth factor in the rat

The distribution of i.v. injected ¹²⁵I-labeled epidermal growth factor (EGF) was examined in the rat. The uptake of radioactivity was examined for the following tissues: liver, kidney, skin, stomach, small intestine, colon, brain, submandibular gland, lung, spleen, and testis. ¹²⁵I-EGF was cleared from the circulation within minutes. At 2.5 min after the injection only 7% of the label was left in the blood. Most of the label was found in the liver (52%), the kidneys (14%), the small intestine (11%) and the skin (7%). The other organs examined contained 1% or less of the radioactivity. The uptake of ¹²⁵I-EGF per g tissue was markedly higher for the liver and kidneys than for the rest of the organs. By autoradiography ¹²⁵I-EGF was found in the peripheral parts of the classical liver lobule, in the proximal tubules of the kidneys, in the surface epithelium of the stomach, and in the surface epithelium of the villi in the small intestine. In conclusion the present study showed that small doses of homologous EGF was cleared from the circulation of rats within minutes, mainly by the liver, the kidneys, and the small intestine.     

The influence of chromium chloride consumption on lipid peroxidation and activity of the antioxidant defense in rat tissues

The effect of food supplementation with chromium (CrCl₃ · 6H₂O) on intensity of peroxide processes and activity of antioxidant enzymes has been investigated in some rat tissues. Food supplementation with 200 μg/kg CrCl₃ · 6H₂O for 30 days resulted in the increase of tissue chromium. The tissue chromium content of chromium-treated rats decreased in the following order: spleen, heart, kidney, lung, brain, liver, skeletal muscles. All organs and tissues (except skeletal muscles) of chromium-treated rats were characterized by decreased content of lipid peroxidation (LPO) products: hydroperoxides and thiobarbituric acid reactive substances (TBARS). The maximal reduction in LPO products was observed in spleen, kidney, liver, and lung. Treatment with chromium also caused an increase in the activity of glutathione peroxidase, glutathione reductase, and calatase in all tissues and organs studied. In the brain and kidney an increase in the content of reduced glutathione was observed. Superoxide dismutase activity was higher in myocardium and skeletal muscles, basically equal in lung and liver, while in other organs (brain, kidney, spleen) of experimental animals it was lower than in control animals. Results of this study suggest that chromium exhibits tissue/organ-specific regulatory effects on enzymes of the antioxidant defense     

A comparison of the binding of endothelin to various tissues from spontaneously hypertensive and Wistar-Kyoto rats

The binding affinities for endothelin-1 and endothelin-3 to membrane preparations of various tissues of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats were compared by competition binding of the peptides with [¹²⁵I]endothelin-1. Endothelin-1 binding data obtained using membrane preparations from brain, heart, kidney, liver, lung and spleen of both strains were better fit with a one-site model. The brain tissue demonstrated the highest affinity for endothelin-1 in both strains with the same IC₅₀ of 0.11 nM, while the kidney and lung tissues showed the lowest affinities in both strains with IC₅₀ values ranged between 1.4 and 4.1 nM. Only the kidney tissues of these two strains showed a statistically significant difference in binding affinities for endothelin-1; the IC₅₀ values were 1.4 ± 0.1 nM (mean ± SE, N = 3) and 3.2 ± 0.4 nM (n = 4) for the spontaneously hypertensive and normotensive rats, respectively. Endothelin-3 binding data obtained using membrane preparations from brain, kidney and lung of both strains were also better fit with a one-site model. In contrast, a two-site model was more suitable for analyzing endothelin-3 binding results obtained using membrane preparations from heart, liver and spleen of both strains. Again, only the kidney tissues of the two strains showed a statistically significant difference in binding affinities for endothelin-3. The ratio of IC₅₀ value of the major endothelin-3 binding site to that of endothelin-1 in each tissue varied from approx. 1.5 in brain, kidney and liver to greater than 500 in heart and spleen of both strains. Scatchard analysis of saturation binding data showed that [¹²⁵I]endothelin-1 bound to a single class of binding sites in brain, heart, liver and spleen of both rat strains and in kidney of the spontaneously hypertensive rats. Specific binding to the kidney membrane preparation of the normotensive rats was not saturable at radioligand concentrations up to about 2 nM. These results suggest that the tissues of both strains investigated have different affinities as well as different selectivities for endothelin-1 and endothelin-3. Furthermore, kidney is the only tissue examined which showed higher binding affinity in the spontaneously hypertensive rats than that of the normotensive ones.     

Increase in production of ascorbate radical in tissues of rat treated with paraquat

The production of ascorbate radical (A^·-) was investigated in tissues of rats intoxicated with paraquat (PQ) to know the protective role of antioxidant ascorbate (AH^·-) in tissues. The electron spin resonance (ESR) method is applied to observe A^·-. To eliminate increased biosynthesis of ascorbic acid (AH₂) by PQ intoxication, ODS rats were chosen and fed with or without 250 ppm PQ in the diet. The radical A^·- was detected only in the lung and spleen homogenates of both intoxicated and control rats at the beginning of ESR measurement. The radical levels of intoxicated rat lung and spleen were increased rapidly to twice the initial level after 3 h and decreased to 0.2–0.6 times the initial level after 24 h, whereas those of control rats were increased slowly to 1.1 times the initial level after 4 h and decreased slowly to 0.7 times the initial level after 24 h at 4°C. In other organs such as liver, kidney, heart and testis, A^·- was not detected initially but detected afterwards. Higher A^·- level was observed in the intoxicated rat liver than the control but no appreciable differences of A^·- levels were observed between the intoxicated kidney, heart and testis and the respective controls. In the intoxicated rat lung the concentration of AH₂ is only half but that of A^·- is twice as high as that of the control. Larger amounts of A^·- produced in the intoxicated rats decayed more quickly than those in the control rats. The simple addition of PQ to the control organ enhanced neither A^·- production nor A^·- quenching. These facts suggest that the tissues damaged by PQ require larger amounts of AH^- to detoxicate harmful oxidants, resulting in concomitant production of A^·-.     

Orotic acid biosynthesis in arginine-deficient rats.

Arginine deficiency is associated with a mild orotic aciduria. Liver slices from rats fed a purified l-amino acid diet with (control) and without arginine supplementation were used for studies of [¹⁴C]bicarbonate incorporation into orotic acid. The nanomoles of orotic acid synthesized in isolated liver slices from both control and arginine-deficient animals increased linearly with time. Orotic acid biosynthesis was significantly greater in liver slices than slices of heart, muscle, kidney, and minced spleen. The order of orotate biosynthesis from [¹⁴C]bicarbonate was liver > spleen = kidney > muscle > heart. Arginine deficiency resulted in a significant stimulation of liver orotic acid biosynthesis. This stimulation in pyrimidine biosynthesis can account for a major portion of the orotic aciduria. Orotic acid synthesis from spleens isolated from arginine-deficient rats was also enhanced compared with controls. Although the rate of orotic acid biosynthesis is small relative to liver production, the spleen may contribute slightly to increased orotic aciduria in the arginine-deficient rat. Arginine supplementation in vitro to livers from rats fed either the control of arginine-deficient diet resulted in a significant reduction in synthesis of orotic acid. Dietary arginine may play a key role in regulating mitochondrial carbamoyl phosphate utilization into both pyrimidine and urea biosynthesis.     

Fate of a liposome-associated agent injected into normal and tumour-bearing rodents. Attempts to improve localization in tumour tissues.

Liposomes containing ¹¹¹In-labelled bleomycin were injected intravenously into normal and tumour-bearing rodents and the fate of radioactivity followed. ¹¹¹In levels in tissues retained their maximum values for up to 48h after treatment thereby enabling accurate estimations of tissue participation which with a variety of tumours (Meth ‘A’, 6C3HED, Lewis lung carcinoma and Novikoff hepatoma) in mice and rats was secondary to that of the liver and spleen. Reductions in the size of liposomes decreased liver and spleen participation and increased tumour and kidney involvement. Uptake by lungs, skeletal muscle and brain was also augmented albeit to a lesser extent. Incorporation of anti-Meth ‘A’ cells IgG immunoglobulin into the liposomal carrier led to a modest increase in the uptake of co-entrapped ¹¹¹In by the Meth ‘A’ tumour implanted subcutaneously. Although at the same time, liposomal IgG reduced uptake by the kidney, it effected a drastic increase in hepatic and splenic involvement. This could be prevented by the concurrent administration of excess “empty” liposomes which, however, did not interfere with uptake by tumour tissue.     

Prostaglandin A2 and S uptake in connective tissue

Rats deficient in essential fatty acids (EFA) incorporated lesser amounts of radioactive sulfate into lung, kidney, spleen, heart, costal cartlidge, long bone and skull bone than did normal control animals. Administration of prostaglandin A₂ stimulated ³⁵S uptake by lung, kidney and aorta while ³⁵S levels in costal cartilage, tibial cap and long bone were strikingly reduced. Comments are presented suggesting that this metabolic mechanism may explain, in part, cartilage and bone resorption in areas of inflammation, such as arthritis, both rheumatoid arthritis and osteoarthritis.     

Prostaglandin A2 and 35S uptake in connective tissue

Rats deficient in essential fatty acids (EFA) incorporated lesser amounts of radioactive sulfate into lung, kidney, spleen, heart, costal cartlidge, long bone and skull bone than did normal control animals. Administration of prostaglandin A₂ stimulated ³⁵S uptake by lung, kidney and aorta while ³⁵S levels in costal cartilage, tibial cap and long bone were strikingly reduced. Comments are presented suggesting that this metabolic mechanism may explain, in part, cartilage and bone resorption in areas of inflammation, such as arthritis, both rheumatoid arthritis and osteoarthritis.     

Grafting of different glycosides on the surface of liposomes and its effect on the tissue distribution of 125I-labelled γ-globulin encapsulated in liposomes

Different glycosides were grafted on the surface of liposomes containing ¹²⁵I-labelled γ-globulin by two ways: (1) by using glycolipid and (2) by covalent coupling of $\text{p-}\text{aminophenyl-}\text{d}\text{-glycosides}$ to phosphatidylethanolamine liposomes using glutaraldehyde. The distribution of ¹²⁵I-labelled γ-globulin was determined in mouse tissues from 5–60 min after a single injection of these liposomes. The liver uptake of encapsulated ¹²⁵I-labelled γ-globulin was highest from liposomes having galactose and mannose on the surface. Competition experiments and cross-inhibition studies indicate that this uptake are mediated by specific recognition of the surface galactose and mannose residues of liposomes by the receptors present on the plasma membrane of liver cells. Stearylamine-containing liposomes were found to be more efficient in mediating the uptake of ¹²⁵I-labelled γ-globulin by the lung, whereas in the case of spleen, phosphatidylethanolamine liposomes were more efficient. The extent of uptake of ¹²⁵I-labelled γ-globulin from all types of liposome decreases as the amount of given liposomes increases. The uptake of ¹²⁵I-labelled γ-globulin from liposomes containing asialogangliosides depends upon the phospholipid/ glycolipid ratio. These experiments clearly demonstrate that enhanced liposome uptake by liver cells could be achieved by grafting galactose and mannose on the liposomal surface.     

Effect of age and dietary protein level on tissue mineral levels in female rats

Mineral (phosphorus, sulfur, potassium, calcium, magnesium, iron, zinc, copper, and manganese) concentrations were measured in plasma, and several tissues from female Wistar rats (young: 3-wk-old; mature: 6-mo-old) were fed on a dietary regimen designed to study the combined or singular effects of age and dietary protein on mineral status. Three diets, respectively, contained 5, 15, and 20% of bovine milk casein. Nephrocalcinosis chemically diagnosed by increased calcium and phosphorus in kidney was prevented in rats fed a 5% protein diet. Renal calcium and phosphorus were more accumulated in young rats than mature rats. A 5% protein diet decreased hemoglobin and blood iron. The hepatic and splenic iron was increased by a 5% protein diet in mature rats but was not altered in young rats. Mature rats had higher iron in brain, lung, heart, liver, spleen, kidney, muscle, and tibia than young rats. A 5% protein diet decreased zinc in plasma and liver. Zinc in tibia was increased with dietary protein level in young rats but was not changed in mature rats. A 5% protein diet decreased copper concentration in plasma of young rats but not in mature rats. Mature rats had higher copper in plasma, blood, brain, lung, heart, liver, spleen, and kidney than young rats. With age, manganese concentration was increased in brain but decreased in lung, heart, liver, kidney, and muscle. These results suggest that the response to dietary protein regarding mineral status varies with age.     

脑红蛋白在赛加羚羊主要内脏器官中的表达与定位

赛加羚羊(Saiga tatarica)属于我国一级重点保护野生动物,其原产地主要为高寒低氧地区,现存种群则主要栖息于中亚地区的荒漠及半荒漠草原上。脑红蛋白是一种存在于脊椎动物体内具有运输和储存血氧能力的球蛋白,在动物适应低氧过程中具有重要的生理功能。为了初步探究赛加羚羊对低氧环境的耐受性机制,运用免疫组织化学染色法与实时荧光定量PCR技术,对脑红蛋白及脑红蛋白基因(NGB)在赛加羚羊的心、肝、脾、肺、肾等5种主要内脏器官中的分布规律与表达情况进行了探究。免疫组织化学染色结果显示,脑红蛋白在赛加羚羊的心、肝、脾、肺、肾中均有分布,阳性表达主要分布在其心肌细胞、肝细胞、脾白髓区中的淋巴细胞、肺泡细胞以及肾小球内皮细胞。实时荧光定量PCR结果显示,脑红蛋白基因在赛加羚羊心、肝、脾、肺、肾中的表达量不同,脾的表达量最高,心的表达量次之,两者均显著高于肝、肺和肾(P < 0.05);其后依次为肝、肾、肺,其中,肝的表达量显著高于肾和肺(P < 0.05),肾和肺之间表达量差异不显著(P > 0.05),肺的表达量最低。上述研究表明,脑红蛋白在赛加羚羊的主要内脏器官中均有阳性表达,不同内脏器官中的表达量不同,这表明脑红蛋白可能参与了这些内脏器官的氧利用过程,具体机制有待进一步探讨。     

Strontium-calcium discriminationin vitro by rat tissues

Uptake of⁸⁹Sr and⁴⁵Ca by 15 soft tissues of adult rat was studiedin vitro to assess the extent of discrimination between Sr and Ca. While brain, kidney, placenta and uterus have lower uptake of⁸⁹Sr and 45 Ca that of diaphragm, lactating mammary gland, skeletal muscle, skin, spleen and testes is higher. Tissues with medium range uptake are heart, small intestine, liver, lung, non-lactating mammary gland and ovary. The 6 tissues displaying discriminating ability, as expressed by⁸⁹Sr/⁴⁵Ca (tissue/medium), in the decreasing order are: small intestine, kidney, lactating mammary gland, placenta, diaphragm and heart. Non-lactating mammary gland and the other tissues did not differentiate between Sr and Ca. The efect of several enzyme inhibitors, compounds influencing Sr-Ca metabolism and other factors was studied in terms of the nature and mechanism of Sr-Ca discrimination.     

In vivo assessment of 111in-labeled hematoporphyrin derivative in breast tumor-bearing animals

The biological behavior of ¹¹¹In-labeled HPD has been investigated in tumor-bearing animals. Mice mammary adenocarcinomas and 7,12-dimethylbenz(a)anthracine induced breast tumors in Sprague-Dawley female rats were clearly visualized by ¹¹¹In-HPD nuclear scintigraphy. Optimal scans were obtained after a 48 h delay. In normal and tumor-bearing animals, the highest uptake of ¹¹¹In-HPD 72 h post-injection was found in the liver, the spleen and the kidneys. Depending on the size and the extent of necrosis, the uptake of ¹¹¹In-HPD by malignant breast tumors varied from 2.5% injected dose (ID) (range 0.14–5.3% ID) in mice to 1% ID (range 0.22–8.1% ID) in rats. Benign breast tumor uptake of ¹¹¹In-HPD was less that 1%ID. No significant amount of the radiopharmaceutical was found in pulmonary abscesses and abdominal cysts (< 0.1 % ID). Scintigrams of these infectious or inflammatory lesions were normal. Malignant tumor to blood, heart and lung ratios averaged 50:1, 10:1 and 3:1 respectively. Tumor to brain ratio ranged from 72 to 444:1.     

Evidence for ceruloplasmin as a copper transport protein.

Rats fed a copper-deficient diet for eight weeks showed a large decrease in cytochrome $\text{c}$ oxidase in heart, spleen, liver, lung, and pancreas but no significant change in kidney and brain. Three injections of human or rat ceruloplasmin over a five day period greatly increased cytochrome $\text{c}$ oxidase activity in spleen, liver, heart and lung. Rats receiving CuCl₂, Cu-histidine, and Cu-albumin produced a smaller and slower increase in cytochrome $\text{c}$ oxidase compared to ceruloplasmin treated animals. In Cu-histidine treated rats, the increase in enzyme activity did not occur until after the plasma ceruloplasmin level reached a maximal value. It is concluded that ceruloplasmin functions as a primary copper transport protein from which copper atoms are transferred to cytochrome $\text{c}$ oxidase and probably other copper containing proteins.     

Distribution and metabolism of iron in muscles of iron-deficient rats

Iron-deficiency anemia leads directly to both reduced hemoglobin levels and work performance in humans and experimental animals. In an attempt to observe a direct link between work performance and insufficient iron at the cellular level, we produced severe iron deficiency in female weanling Sprague-Dawley rats following five weeks on a low-iron diet. Deficient rats were compared with normal animals to observe major changes in hematological parameters, body weight, and growth of certain organs and tissues. The overall growth of iron-deficient animals was approximately 50% of normal. The ratio of organ weight: body weight increased in heart, liver, spleen, kidney, brain, and soleus muscle in response to iron deficiency. Further, mitochondria from heart and red muscle retained their iron more effectively under the stress of iron deficiency than mitochondria from liver and spleen. Metabolism of iron in normal and depleted tissue was measured using tracer amounts of⁵⁹Fe administered orally. As expected, there was greater uptake of tracer iron by iron-deficient animals. The major organ of iron accumulation was the spleen, but significant amounts of isotope were also localized in heart and brain. In all muscle tissue examined the⁵⁹Fe preferentially entered the mitochondria. Enhanced mitochondrial uptake of iron prior to any detectable change in the hemoglobin level in experimental animals may be indicative of nonhemoglobin related biochemical changes and/or decrements in work capacity.     

Investigation on Toxicity and Teratogenicity in Rats of a Retinoid‐Polyamine Conjugate with Potent Anti‐Inflammatory Properties

Previous studies have shown that N¹,N¹²‐bis(all‐trans‐retinoyl)spermine (RASP), a retinoid analog, inhibits RNase P activity and angiogenesis in the chicken embryo chorioallantoic membrane, demonstrates anti‐tumor activity on prostate cancer cells, and acts as anti‐inflammatory agent, being more effective and less toxic than all‐trans retinoic acid. In an attempt to further characterize the biological profile of RASP, we tested its effects on organ toxicity and teratogenicity by daily oral gavage of RASP at a level of 50 mg/Kg of body weight in two generations of rats. We found that this compound does not induce changes to the body growth, the appearance of physical features, and the animal's reflexes. Additionally, no substantial histopathological lesions were found in brain, heart, lung, thymus, liver, thyroid gland, adrenal gland, pituitary gland, kidneys, spleen, skin, femora, prostate, testis, epididymis, vagina, uterus, and ovaries of RASP‐treated animals. These results suggest RASP, as a promising lead compound for the treatment of several dermatological disorders and certain cancer types, has apparently minimal toxic side‐effects as revealed in this two‐generation reproduction study in rats.     

Effects of iron deficiency and iron overload on manganese uptake and deposition in the brain and other organs of the rat

Managanese (Mn) is an essential trace element at low concentrations, but at higher concentrations is neurotoxic. It has several chemical and biochemical properties similar to iron (Fe), and there is evidence of metabolic interaction between the two metals, particularly at the level of absorption from the intestine. The aim of this investigation was to determine whether Mn and Fe interact during the processes involved in uptake from the plasma by the brain and other organs of the rat. Dams were fed control (70 mg Fe/kg), Fe-deficient (5–10 mg Fe/kg), or Fe-loaded (20 g carbonyl Fe/kg) diets, with or without Mn-loaded drinking water (2 g Mn/L), from day 18–19 of pregnancy, and, after weaning the young rats, were continued on the same dietary regimens. Measurements of brain, liver, and kidney Mn and nonheme Fe levels, and the uptake of⁵⁴Mn and⁵⁹Fe from the plasma by these organs and the femurs, were made when the rats were aged 15 and 63 d. Organ nonheme Fe levels were much higher than Mn levels, and in the liver and kidney increased much more with Fe loading than did Mn levels with Mn loading. However, in the brain the increases were greater for Mn. Both Fe depletion and loading led to increased brain Mn concentrations in the 15-d/rats, while Fe loading also had this effect at 63 d. Mn loading did not have significant effects on the nonheme Fe concentrations.⁵⁴Mn, injected as MnCl₂ mixed with serum, was cleared more rapidly from the circulation than was⁵⁹Fe, injected in the form of diferric transferrin. In the 15-d-rats, the uptake of⁵⁴Mn by brain, liver, kidneys, and femurs was increased by Fe loading, but this was not seen in the 63-d rats. Mn supplementation led to increased⁵⁹Fe uptake by the brain, liver, and kidneys of the rats fed the control and Fe-deficient diets, but not in the Fe-loaded rats. It is concluded that Mn and Fe interact during transfer from the plasma to the brain and other organs and that this interaction is synergistic rather than competitive in nature. Hence, excessive intake of Fe plus Mn may accentuate the risk of tissue damage caused by one metal alone, particularly in the brain.     

Effects of dietary supplementation with aluminum and citrate on iron metabolism in the rat

The metabolism of iron (Fe) has been shown to interact with that of aluminum (Al) in relation to intestinal absorption, transport in the blood plasma, and the induction of lipid peroxidation and cellular damage. Also, dietary supplementation with citrate has been shown to increase the absorption of both metals and, in the presence of high intakes of Fe and Al, leads to excessive accumulation of both metals in the body. In this study, the likely interaction between Al and internal Fe metabolism was investigated using rats fed diets that were either deficient, sufficient, or loaded with Fe, with or without the addition of Al and sodium citrate. These diets commenced when the rats were 4 wk old and were continued for 9–11 wk. At that time, Fe metabolism as assessed by measurement of organ uptake of⁵⁹Fe and¹²⁵I-transferrin, after iv injection of transferrin labeled with both isotopes, plus measurement of tissue concentrations of nonheme Fe and Al. The Fedeficient diet and Fe-loaded diet led to states of Fe deficiency and Fe overload in the rats, and supplementation of the diet with Al increased Al levels in the kidneys, liver, and femurs, but, generally, only when the diet also contained citrate. Neither Al nor citrate supplementation of the diet had any effect on nonheme Fe concentrations in the liver, kidney, or brain, or on the uptake of⁵⁹Fe or¹²⁵I-transferrin by liver, kidney, brain, or spleen. Only with the femurs was a significant effect observed: increased⁵⁹Fe uptake in association with increased Al intake. Therefore, using this animal model, there was little evidence for interaction between Fe and Al metabolism, and no support was obtained for the hypothesis that dietary supplementation with Fe and citrate can lead to excessive Fe absorption and deposition in the tissues.     

The effect of felodipine on the uptake and degradation of acetylated LDL in mouse peritoneal cells and on the distribution of acetylated LDL in macrophage-rich organs of the rat

The effect of felodipine on lipoprotein metabolism ex vivo and in vivo was investigated. In the ex vivo studies mice were given felodipine (40–125 μ mol/kg body weight) or vehicle for one week. Peritoneal macrophages from these animals and controls were isolated and used in binding and degradation studies with human iodinated acetylated LDL (Ac-LDL). Macrophages from felodipine-treated mice showed a significant decrease of binding and degradation of Ac-LDL compared to macrophages from control animals (P<0.05). The in vivo studies were performed in rats pretreated with felodipine or vehicle. To determine the distribution and plasma turnover of LDL and Ac-LDL, ¹²⁵I-tyramine cellobiose labelled LDL or Ac-LDL were given i.v. No differences in the removal rate of Ac-LDL or LDL were observed between felodipine-treated or untreated rats. However, an increased uptake of Ac-LDL could be seen in the liver of the felodipine-treated rats. This increased uptake could be ascribed to the parenchymal cells because no differences in uptake could be seen in the liver endothelial cells. However, a significant decreased uptake was seen in the Kuppfer cells and in the spleen, a macrophage-rich organ, of the felodipine-treated rats. The present study suggests a possible mechanism behind the antiatherogenic effects of calcium antagonists, a decreased uptake of atherogenic modified lipoproteins by peripheral macrophages and an increased uptake by the liver.     

Tissue distribution of hepatocyte growth factor receptor and its exclusive down-regulation in a regenerating organ after injury.

Using 125I-labeled hepatocyte growth factor (HGF) as a ligand, we examined the tissue distribution of the HGF receptor in adult rats. Specific binding of 125I-HGF was detected in the plasma membranes of liver, spleen, kidney, lung, adrenal gland, pituitary, and thyroid. Scatchard analysis of HGF binding in liver, spleen, kidney, lung, and adrenal gland revealed the presence of a single class of high affinity receptor with a dissociation constant (Kd) of 20-30 pM. The maximum number of binding sites (Bmax) was determined to be 400-3,000 sites per ng of plasma membrane protein, the highest number being in the liver. Such a wide distribution of a high affinity HGF receptor indicates that HGF may be a multifunctional growth factor, targeting to a variety of organs, and not restricted to liver. After 70% partial hepatectomy, specific binding of 125I-HGF to membranes of the residual liver rapidly decreased, but there was no change in the kidney, lung, and spleen. On the other hand, after unilateral nephrectomy rapid down-regulation of the HGF receptor was clearly evident in the remaining kidney, but not in other organs including the liver. These findings suggest the presence of control mechanisms governing HGF receptor function only in a regenerating organ after injury.