Postmortem changes in myoglobin content in organs

Postmortem changes in myoglobin concentrations in blood and organs were investigated using an enzyme immunoassay by animal experiments in combination with immunohistochemical staining of human cases. Blood myoglobin concentrations were found to increase drastically within a very short time after death. Those in striated muscle, however, did not change by day 14 postmortem. Myoglobin content in the liver and kidney increased slightly by day 5 postmortem, and more obviously by day 7 or later. However, almost no change was observed by day 5 in the kidney when the renal artery and vein had been ligated just after death. In the thyroid gland and the lung, the myoglobin content markedly increased by day 7 postmortem, with the logarithmical values rising nearly linearly as the time after death passed. In the thyroid gland, concentrations reached the level of the striated muscle. The mechanisms of postmortem myoglobin increase in organs are thought to be direct diffusion from the striated muscle and/or distribution through the blood. To estimate the postmortem interval, the determination of myoglobin content in the thyroid gland or the lung appears to be useful.     

Reversible hyperplasia and hypertrophy of the mouse liver induced by a functional charge with phenobarbital]

Introduction: Administration of phenobarbital to rats and mice is well known to cause enlargement of the liver, where the drug is metabolized by hydroxylation and oxydation. The increase of the liver weight is thought to be due to and enlargement of the individual hepatocytes (hypertrophy) caused by an augmentation of the smooth endoplasmic reticulum, as well as to cell multiplication (hyperplasia). The present investigation deals with the nuclear DNA content of mouse hepatocytes during and after administration of different doses of phenobarbital. The data are related to liver weight with due consideration of mitotic activity and cell loss by necrobiosis. Material and Methods: 172 five to six weeks old male albino NMRI mice with a body weight of 23 to 33 gms were randomly divided into four groups, one of which served as the controls. The three test groups received 75 mg and 150 mg phenobarbital per 1 kg body weight intraperitoneally once every day for a total of 10 days. Thereafter the administration of the drug was discontinued. Beginning with the third day of the experiment 3 animals of each group were sacrificed by exsanguination every secound day after their body weight had been carefully determined. Then the liver weights were measured. The nuclear DNA content of the hepatocytes was determined from liver smears by means of acriflavine-Feulgen fluorescence cytophotometry. The number of mitotic figures and of necrobiotic liver cells was counted in histologic sections. Results: With animals receiving 150 mg and 100 mg phenobarbital per 1 kg body weight a rapid increase of the relative liver weight (up to 74% above the controls) was observed, which was reduced back to normal levels within 10 days after discontinuation of the drug. Parallel with the increase of the liver weight a striking DNA-polyploidisation of the liver nuclei occurred which proved to be reversible during the reduction phase. Mitotic figures were found only in the initial phase of the experiment (third to fifth day), while the number of necrobiotic hepatocytes was increased after the drug was discontinued. Similar but markedly less pronounced effects were encountered with animals of the 75 group. Discussion: It is concluded that the increase of the liver weight of mice after phenobarbital administration is partly due to cell multiplication (hyperplasia) - as is shown by a high number of mitotic figures in the initial phase of the experiment-, partly due to the enlargement of hepatocytes with concommitant polyploidisation of the muclei (hypertrophy). When the drug administration is discontinued the liver weights return to normal levels within 10 days. Since at the same time the number of high-ploidy nuclei is reduced with no evidence of an increased mitotic activity, the reduction of the liver weight should be partly caused by an elimination of high-ploidy hepatocytes, which are no longer required after the hyperfunctional stimulus has ceased...     

DNA, RNA and total protein content of leg and breast muscles of White Rock chickens selected for 56-day body weight

Pectoralis and gastrocnemius muscles from White Rock chickens divergently selected for 29 generations for high or low 56-day body weight were analyzed for DNA, RNA and protein (mg/g) content at 12 ages between hatch and 273 days of age. Dimorphism between lines was maximum at day 18 for both muscle types and then declined with age. High-line chickens generally deposited relatively more muscle tissue than those from the low line. Although nonadditive genetic variation was evident for absolute muscle weights, it was more frequent for muscle weight relative to body weight. For both muscle types, DNA unit number, as measured by DNA content (mg/g), was larger for the high line than the low immediately after hatch and smaller in the high than in the low line from day 10 to 56 after which lines were similar. RNA and protein/g muscle were similar for both lines at most ages. Between days 4 and 56, a period of rapid muscle growth, DNA unit size (protein/DNA) of both muscle types was larger in the high than in the low line. Heterosis was positive for protein, DNA unit number and size, and negative for RNA content. While weight of pectoralis muscle was similar to that of one gastrocnemius muscle on day 1, by day 273 its weight was over 3-fold greater. DNA unit number was higher in pectoralis than gastrocnemius muscle from hatch to day 4, similar on days 7 and 10 and lower for pectoralis muscle beyond day 10. RNA content was similar at all ages except 4, 7 and 10 days. DNA unit size followed the same pattern as DNA unit number; however, greater nuclei number at hatch for the high line corresponded with low DNA unit size. This pattern suggests a higher rate of cellular filling for pectoralis than gastrocnemius muscle.     

Liver regeneration and immune system--morphological and cytochemical studies of activated spleen cells during the liver regeneration after partial hepatectomy

Morphological and cytochemical changes were investigated in spleen cells after 70% hepatectomy in mice. During liver regeneration after the hepatectomy, the spleen weight gradually rose to a peak at 6 day. In the spleen, the number of POD-positive myelocytic cells and NCAE-positive granulocytic cells also reached a peak 4 days after the operation and then decreased. On the other hand, ANBE-positive monocytic cells gradually increased up to 9 day and didn't decrease for this period. On day 9 of the culture, the boundary between the red and the white pulps of the spleen became unclear. In this spleen, the clusters of blast cells were sporadically observed. Splenic T cells cocultured with nonparenchymal adherent normal liver cell or nonparenchymal adherent normal liver cell supernatant developed into granulocyte colonies in earlier periods and monocyte colonies in later periods. These findings suggest that the factors released from liver cells may regulate strictly spleen cell activation. Blast cell formation in the culture with nonparenchymal adherent normal liver cell supernatant was amplified by anti interferon (alpha + beta) antibody. These facts indicate that the functional network of cytokines is formed by the interaction of various cytokines (IL-1, IL-6, CSF, IFN, etc.) in nonparenchymal adherent normal liver cell supernatant.     

Theophylline increases the uptake of radioiodine by mouse thyroid

Diagnostic and therapeutic use of radioiodine in the management of thyroid disorders depends on the ability of thyroid cells to concentrate radioiodine, a process that is regulated by the intracellular increase in cAMP. We hypothesized that theophylline, a drug known to increase intracellular cAMP via inhibition of phosphodiesterase, could increase thyroidal radioiodine uptake. We tested this effect in vivo, using C57BL/6j mice, and in vitro, using Fisher rat thyroid (FRTL-5) cells. One mouse received 2.5mg theophylline i.p., whereas a control mouse received only saline. Twenty-hours after theophylline, mice were injected with 10 microCi Na125I in 0.1 mL saline through the tail vein. Mean thyroidal 125I activity was 3.3-fold higher in theophylline-treated mice than in their respective controls. Radioiodine uptake and intracellular cAMP production of FRTL-5 cells were increased by a relatively low concentration of theophylline (1 microM). Intracellular cAMP increased up to 30 min and then declined in response to 1 microM theophylline. Sera from theophylline-treated mice stimulated 125I uptake and intracellular cAMP production by FRTL-5 cells. These findings show that theophylline can enhance radioiodine uptake by thyrocytes in vivo and in vitro. The in vitro effects of theophylline on both radioiodine uptake and cAMP production in a dose-dependent manner are consistent with an action mediated by phosphodiesterase inhibition.     

Comparative biochemical and morphometric changes associated with induction of the hepatic mixed function oxidase system in the rat.

This study characterized the induction of the rat hepatic cytochrome P-450-dependent mixed function oxidase system by SK&F 86002 [6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-(2,1-b)thia zole], an inhibitor of both the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The induction characteristics of SK&F 86002 were compared to those of the classical inducer, phenobarbital, and morphological features of both SK&F 86002 and phenobarbital induced hepatocellular hypertrophy were quantitated. Rats were administered either SK&F 86002 (6, 18, or 60 mg/kg/day, po) or phenobarbital (8, 24, 80 mg/kg/day, ip) for 3 or 14 consecutive days. Liver to body weight ratio, total hepatic microsomal protein and cytochrome P-450 content, ethoxycoumarin-O-deethylase (ECOD) and leukotriene B4(LTB4) omega- and omega-1 hydroxylase were measured. Ultrastructural morphometry of the liver from control, and high dose SK&F 86002 (60 mg/kg/day) and phenobarbital (80 mg/kg/day) treated rats was completed. On day 3, phenobarbital increased liver to body weight ratio but only at the 80 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity increased in a dose-dependent fashion. LTB4 omega- and omega-1 hydroxylase activities were unaffected. Administration of SK&F 86002 for 3 days increased the liver to body weight ratio at both the 18 and 60 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity was significantly increased by the 60 mg/kg/day dosages of SK&F 86002. On day 14, phenobarbital increased the liver to body weight ratio and microsomal protein content but again only at the 80 mg/kg/day dosage. Cytochrome P-450 content was increased by all dosages.(ABSTRACT TRUNCATED AT 250 WORDS)     

Toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil

Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for triadimefon. Male Wistar/Han rats were treated with triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were present only after 30 days in rats treated with the high dose of triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of propiconazole and triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days. Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for triadimefon-induced thyroid gland tumors was not supported by the data.     

Ornithine decarboxylase activity, nucleic acids and cell turnover in the livers of pregnant rats

1. Comparisons were made between the livers of pregnant and non-pregnant rats, all of which were fed on a ration of 20 g food per day.2. In the second half of pregnancy there were marked increases in the weight of the liver and in its total content of protein, RNA and DNA. RNA concentration increased from the 15th day of gestation.3. Between the 12th and 18th day of pregnancy liver weight, total RNA, totla DNA and mean liver cell nuclear volume increased in parallel at approximately the same rate of 6-10% per day.4. Ornithine decarboxylase activity was enhanced in pregnancy by the 5th day of gestation and rose to peak activity at the 18th day.5. The mitotic index of hepatic parenchymal cells was elevated in the first and last stages of pregnancy. The later peak in mitosis was associated with a rapid fall in mean nuclear volume.6. There was histological evidence of cell turnover in the liver of pregnant rats; enlargement of the liver was associated with both hyperplasia and cell deletion.     

Effect of partial hepatectomy on the number of somatotrophs in the rat adenohypophysis

Two-thirds of the liver was removed by the method of Higgins and Anderson from male rats weighing 100–150 g. The adenohypophyses from rats undergoing partial hepatectomy or a mock operation or from rats left intact were studied 2, 4, 8–10, and 25 h and 2, 3, 6, 10, 14, and 21 days after the operation. A significant increase in the number of somatotrophs was found 8–10 h after partial hepatectomy, but 25 h after the operation they were fewer in number than in rats undergoing the mock operation. The number of somatotrophs in the adenohypophysis of the partially hepatectomized rats returned to normal on the second day after the operation and there-after remained substantially unchanged. The results suggest that somatotrophic hormone plays a role in the regulation of repair processes in the liver.     

Effect of preceding stress on mitotic activity of the regenerating liver

For 2 h male rats were immobilized 14 h or 24 h before partial hepatectomy. Some of these animals received subcutaneous injections of theophylline immediately after immobilization and next day. Under the influence of stress a tendency was observed for mitotic activity of the regenerating liver to be increased. This effect was particularly marked in rats receiving theophylline additionally.Department of Physiology of Animals, N. G. Chernyshevskii Saratov University. Central Research Laboratory, Saratov Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR A. P. Avtsyn.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 10, pp. 1254–1255, October, 1976.     

The pathologic response of the liver and thyroid of the rat to potassium prorenoate (SC-23992)

A 3-month dose range finding study in preparation for a 2-yr carcinogenicity study of potassium prorenoate (SC-23992), a steroid with an antihypertensive profile, is reported. The drug was administered by gavage once daily at doses of 10, 30, and 100 mg/kg/day to Charles River CD rats. Treatment was terminated at 13 weeks and 10 randomly selected animals from each treatment group were killed and necropsied. The remaining 10 animals in each dose group, including controls, were maintained for an additional 4 weeks, in order to investigate reversibility of changes, and then were killed and necropsied. Dose-related increases in thyroid-stimulating hormone (TSH) levels were observed in treated animals of both sexes during the dosing period and the changes were statistically significant and correlated with an increased thyroid weight in females at 13 weeks. Dose-related morphologic changes in the thyroid, observed by light and electron microscopy, were compatible with the effects of TSH stimulation. Liver weights, which increased, were dose-related. In females the increase was statistically significant at the high dose at 2, 4, and 13 weeks. In males it was significant at the high dose at 13 weeks. Microsomal enzyme levels were increased in a time- and dose-related manner with higher values in females than in males. The pattern of enzyme induction was of the type exemplified by pregnenolone- 16-alpha-carbonitrile. Morphologic changes in the liver showed centrilobular hepatocyte enlargement with smooth endoplasmic reticulum membrane proliferation confirmed by electron microscopy. All positive findings returned to normal after the 4-week treatment-free period. The relationship between the thyroid stimulation to liver enzyme induction is of interest. Evidence is presented here that in the presence of SC-23992, TSH stimulation and liver enzyme induction occurred. The possibility that the liver metabolism stimulates the thyroid T3, T4 elimination with secondary TSH activity is a possible explanation, but on the basis of existing information, direct action by SC-23992 on the thyroid cannot be excluded.     

The effects of aminotriazole (ATZ) on the thyroid gland and the development of the White Leghorn chick.

White Leghorn chicks, injected i.p. (days 3 through 40) with 0.5 g/kg or 1.0 g/kg mean body weight of aminotriazole (ATZ), gained less weight than the control animals. In the 1.0 g/kg ATZ group in comparison to the 0.5 g/kg animals, the responses were of greater magnitude and for longer durations of time. In both experimental groups, the thyroid/body weight ratios increased and were greater than those of the controls after day 10. In the higher dosage group, these ratios increased markedly, whereas with the lower dosage group, the ratios stabilized at a lower value. Histological alterations of the thyroid included hypertrophy, hyperplasia and hyperemia. To study the effect of cessation of drug treatment, groups of animals received the same dosages of ATZ through day 20. At the termination of the experiment (day 41), this resulted in a sharp increase in body weight, experimentals weighing as much as or more than the controls. Regarding the decrease in thyroid/body weight ratios, experimentals never attained the low control values. However, upon cessation of drug treatment, a return towards normal thyroid histology was noted. The gross body weight, the thyroid/body weight ratios, the histological analyses of the thyroidal components and the triiodothyronine and thyroxine determinations in the blood serum demonstrate that ATZ is a potent goitrogenic agent which produces a state of functional hypothyroidism.     

Induction of suppressor T cells in asthmatic children by theophylline treatment

The absolute T-cell numbers and function, and the T-suppressor-cell subset were tested in eleven children with extrinsic asthma prior to and 1 month after theophylline treatment. Low mean T-suppressor-cell number and function was found in the asthmatic children, which returned to normal levels and function after 1 month of theophylline treatment. A normal mean T-cell number was found in this group of children prior to, and 1 month after, theophylline treatment. An obvious correlation between the clinical severity of the asthma and the number of T suppressor cells was found. It is suggested that theophylline most probably activated the T suppressor cells in the asthmatic children.     

3,4,3',4'-tetrachlorobiphenyl-induced effects in the rat liver. I. Serum and hepatic retinoid reduction and morphologic changes

The distribution of 3,4,3',4'-tetrachlorobiphenyl (TCB), its effects on serum and hepatic retinoid, content and liver morphology were investigated in adult female WAG/Rij rats. Animals received a single intraperitoneal injection of either a corn oil vehicle, 15 or 200 mg TCB/kg body weight and were killed at 1, 3, 7, and 14 days after treatment. One rat of the high-dose group that had received 200 mg TCB/kg containing 1.85 mCi of 3H-TCB was sacrificed at each sampling time. There was a significant increase in liver weight when expressed as a percentage of body weight in the high-dose group at day 3 (122% of controls), day 7 (116% of controls), and day 14 (110% of controls). There was a rapid rise in the amount of 3H-TCB present in the liver that peaked at day 7 followed by a rapid decline in the amount of radiolabelled material by day 14. Greater than 90% of the radiolabelled material in the liver was parent compound. TCB treatment induced a significant decrease in serum retinol content in the high-dose group at day 3 (39% of controls) and day 7 (46% of controls) following exposure. There was a significant decrease in hepatic retinol content in the high-dose group at day 3 (34% of controls), day 7 (25% of controls), and day 14 (42% of controls) following exposure. TCB treatment induced a significant decrease in hepatic retinyl palmitate content in the high-dose group at day 7 (56% of controls) following exposure. Ultrastructural alterations in hepatocytes included the proliferation and vesiculation of endoplasmic reticulum, and mitochondrial enlargement with paracrystalline inclusions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ontogeny of the pituitary-thyroid system in fetal rats: Observations on the fetal thyroid after maternal treatment with goitrogen

The critical time of onset of the reciprocal relationship between the pituitary and the thyroid in fetal rats was assessed by the appearance of goiters in fetuses after maternal treatment with goitrogen, propylthiouracil (PTU), on various days of gestation. The assessment was based on changes in the weight and histology of the fetal thyroids. The day following overnight mating was regarded as day 1 of gestation. Pregnant rats were treated with 40 mg PTU each day for two days and autopsied on the third day. The various experimental periods were days 16–18, 17–19, 18–20, 19–21, and 20–22. PTU given to pregnant rats on days 16 and 17 did not cause any change in the fetal thyroids. PTU given on days 17 and 18 caused only a slight increase of fetal “thyroid weight/body weight” ratio. In all other experimental periods (days 18–20, 19–21, and 20–22), PTU induced conspicuous goiters in fetuses, which was reflected by an increased weight of thyroids, an increased height of follicular cells, and a decreased amount of colloid stored in follicles. The results suggest that in fetal rats, the reciprocal relationship between the pituitary and the thyroid is established on approximately days 19–20 of gestation.     

Modulation of thyroidal radioiodine uptake by theophylline

Diagnostic and therapeutic use of radioiodine in the management of thyroid disorders depends on the ability of thyroid cells to concentrate radioiodine, a process regulated by thyrotropin and dependent on the intracellular increase in cAMP. We tested the ability of theophylline, a drug known to increase intracellular cAMP via inhibition of phosphodiesterase, to modulate the thyroidal radioiodine uptake in FRTL-5 cells, in mice and in humans. In FRTL-5 cells, theophylline increased the uptake of radioactive iodine and intracellular cAMP only at low concentrations (1 microM). In mice, theophylline increased slightly the radioiodine uptake, although this increase varied from 1.5- to 6.6-fold. In humans, theophylline decreased slightly the radioiodine uptake, a decrease that became more pronounced with time after radioiodine administration. These studies suggest that theophylline modulates the radioiodine uptake in a dose-dependent fashion, although the modulation is mild and probably not applicable to the clinical setting.     

Immunocytochemical localization of thyroid hormone nuclear receptors in cultured acetylcholinesterase-positive neurons: a correlation between the presence of thyroid hormone nuclear receptors and L-tri-iodothyronine morphological effects.

A monoclonal antibody against the rat liver L-tri-iodothyronine nuclear receptor and acetylcholinesterase cytochemistry were used for the localization of thyroid hormone nuclear receptors in acetylcholinesterase-positive cell nuclei in fetal rat cerebral hemisphere neuronal cultures. After 3 days in vitro, the ratio of acetylcholinesterase-positive cells that were immunoreactive for the thyroid hormone nuclear receptor to those not stained for this receptor (74-26%, respectively) remains unchanged despite an increase in the number of acetylcholinesterase-positive cells with time (from day 3 to day 21) in culture. Furthermore, the addition of 3 X 10(-8) L-tri-iodothyronine in culture did not modify this ratio or have an effect on the number of acetylcholinesterase-positive cells, but significantly increased the neurite density in those acetylcholinesterase-positive cells that were immunoreactive for the thyroid hormone receptor. Conversely, no difference in the neurite densities of those acetylcholinesterase-positive cells not stained for this receptor was observed when cultured in the presence or absence of thyroid hormone. In other experiments with the same fetal brain cultures, treatment of cultures for 8 days with L-tri-iodothyronine, beginning on culture day 20, demonstrated the presence of a critical period which occurs in vitro around day 20, since the stimulatory effect of L-tri-iodothyronine on immunoreactive acetylcholinesterase-positive cell neurite density is lost after 20 days in vitro. These results demonstrate, for the first time, the presence of L-tri-iodothyronine nuclear receptors in fetal rat acetylcholinesterase-positive neurons and the existence of a cellular heterogeneity in the distribution of the thyroid hormone receptor. The presence of these receptors in fetal brain acetylcholinesterase-positive neurons suggests that some effects of L-tri-iodothyronine on the maturation of a subpopulation of acetylcholinesterase-positive neurons may result from a direct effect of this hormone through an interaction with its specific nuclear receptors.     

The effects of age on the pharmacokinetics and biotransformation of theophylline in vivo and in vitro in the Mongolian gerbil (Meriones unguiculatus).

The effect of post maturational aging on the in vivo disposition of theophylline was examined in the Mongolian gerbils (Meriones unguiculatus) aged 30-39 (old), 12-18 (middle-aged) and 3 (young) months following a 20 mg/kg i.p. dose. Biotransformation of theophylline was also examined in liver microsomes from non-induced and 3-methylcholanthrene induced gerbils. Analysis of theophylline plasma kinetics showed decreased clearance, increased half-life and increased volume of distribution in old vs. young animals. Clearance to the 1,3-dimethyluric acid metabolite was similar for all age groups, while clearance to the 1-methyluric acid metabolite was significantly lower in the middle-aged group compared to that of young and old gerbils. Urinary recovery of 1-methylurate was increased in old vs. young and middle-aged animals while recovery of theophylline was decreased. 3-Methylcholanthrene induction resulted in decreased recovery of theophylline and increased recovery of 1,3-dimethylurate and 1-methylurate in young and middle-aged gerbils compared to non-induced controls. Decreased microsomal protein content was observed in old vs. young and middle-aged gerbils and an age-related decrease in cytochrome P-450 content (nmol P-450/g liver) was also observed. The rate of dimethylurate formation was decreased 37% in microsomes from old vs. young and middle-aged gerbils. 3-Methylcholanthrene administration resulted in a 2- and 1.5-fold increase in the rate of 1,3-dimethylurate formation in young and middle-aged gerbils, respectively. The results of these experiments indicate that the Mongolian gerbil may be useful for the study of the biochemical mechanisms underlying age-related changes in the biotransformation and kinetics of theophylline.     

Formation of granulomas in liver of silica-treated rats

Hepatic silicosis was induced in rats by an intravenous injection of saline-suspended silica, 40 mg/kg of body weight. Changes in the liver were examined by biochemical, histological and histochemical methods. Infiltration of the liver parenchyma by polymorphonuclear leucocytes was observed only on the first day after silica treatment. Formation of silicotic nodules began on the first day by clustering of liver macrophages. A 22% increase in liver weight and a 67% increase in total liver DNA reflected accumulation of cells in the liver by day 28 after silica injection. Local cell division contributed to this increase. Almost all cells in the nodules contained carbon when the rats had been given ink before silica. Macrophages showed high activity of lysosomal esterases on the first few days after silica treatment; the activity disappeared later. Large granulomas containing hundreds of cells including lymphocytes were seen 226 days after treatment. Hydroxyproline content per gram of liver tissue increased by 35% and 58% by day 80 and 162, respectively. Connective tissue formed capsules around the nodules and grew to their inside. Activities of lysosomal enzymes, beta-D-galactosidase and acid proteases, in serum were increased by 20% and 300%, respectively, 35 days after treatment. Neither malondialdehyde concentration nor superoxide dismutase activity was elevated in silicotic liver.