Glucocorticoid inhibition of inflammation-induced metallothionein synthesis in mouse liver.

The effects of glucocorticoid treatment on the induction of hepatic metallothionein (MT) during inflammation initiated by turpentine oil (TUR) or endotoxin (LPS) were studied in mice. The administration of TUR increased concentrations of hepatic MT as well as that of plasma fibrinogen. Although hepatic MT was modestly induced by dexamethasone (DEX) alone, pretreatment with DEX (12.5 to 100 mg/kg, sc) inhibited the increases both in hepatic MT and in plasma fibrinogen from a subsequent dose of TUR 6 hr after DEX administration. The concentration of hepatic MT in the DEX-pretreated (25 mg/kg) group was higher than that in the nonpretreated group 4 hr after administration of TUR, but after 24 hr, the MT concentration in the DEX-pretreated group was inhibited to 20% of that in the nonpretreated group. These inhibitory effects were also observed by prednisolone (PRE) but not by salicylic acid. The inhibitory effect of DEX on the induction of MT synthesis during inflammation was observed after administration of the exudate obtained from inflamed tissue. When inflammation was initiated by an injection of LPS as well as TUR, pretreatment of either DEX or PRE inhibited the increase of hepatic MT. Pretreatment of DEX did not affect the induction of hepatic MT synthesis by cadmium. In contrast to inflammation initiated by TUR or LPS, pretreatment of DEX caused an additive increase of hepatic MT concentration after administration of zinc. These results suggest that glucocorticoids, despite being direct inducers of MT, inhibit the induction of MT synthesis during inflammation by the suppression of cytokine production.     

Correlation of hepatic metallothionein concentrations with acute cadmium toxicity in the mouse

Dose-dependent induction of metallothionein by cadmium was measured by gel filtration of liver supernatants prepared from mice 48 hr following single doses of 0.2–2.0 mg of Cd/kg (ip). Hepatic metallothionein concentrations increased in proportion to the cadmium pretreatment dose. A dose-dependent tolerance to acute cadmium toxicity was simultaneously evidenced by elevated LD50 values in cadmium-pretreated mice. A positive correlation between dose-related increases in hepatic metallothionein and cadmium LD50 suggests a protective function for metallothionein. The data suggest that a threshold dose of cadmium must be exceeded in order to induce concentrations of metallothionein adequate to ameliorate acute cadmium toxicity.     

Induction of hepatic metallothionein by trivalent cerium: role of interleukin 6

Metallothionein (MT) is a small sulfydryl-rich protein that binds to and is inducible by heavy metals such as mercury, cadmium, zinc, and copper. However, little is known about the induction of MT by trivalent metals except for bismuth. In this study, we examined the induction of MT synthesis by cerium, a trivalent lanthanoid metal. Administration of cerium chloride (CeCl3) to mice resulted in accumulation of cerium and induction of MT in the liver in a dose-dependent manner. Distribution profiles of metals in the soluble fraction of the liver of CeCl3-treated mice analyzed by high performance liquid chromatography/inductively coupled argon plasma-mass spectrometry (HPLC/ICP-MS) demonstrated that the metal bound to MT-I and MT-II was zinc, but not cerium. Administration of CeCl3 caused increases in the activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the levels of serum amyloid A (SAA), an acute phase protein. Among inflammatory cytokines examined, interleukin 6 (IL-6) exhibited a marked increase in the serum at 3 h after the CeCl3 administration. In order to evaluate the involvement of IL-6 in the induction of MT by cerium, we examined MT induction by CeCl3 in IL-6 null mice. Both the induction of hepatic MT and the increases in SAA levels were markedly suppressed in IL-6 null mice. These results suggest that IL-6 plays an important role in the induction of hepatic MT by cerium.     

Induction of metallothionein by steroids in rat primary hepatocyte cultures

The purpose of this study was to characterize the induction of metallothionein (MT) by steroids in rat primary hepatocyte cultures. Comparison of the characteristics of MT induction by a steroid (dexamethasone) to that by metals (Zn and Cd), examination of the involvement of the glucocorticoid receptor in the steroid induction of MT, and determination of the potency and effectiveness of a number of steroids were studied. In general, the patterns of MT induction by metals and steroids were quite different. For metals, the maximal MT induction (12- to 39-fold) was limited by toxicity whereas for steroids, a plateau in MT induction (fivefold) occurred at noncytotoxic concentrations. Steroids elicited an increase in MT at concentrations that were one-hundredth to one-thousandth less than that of metals. A combination of metal and steroid increased the induction of MT to a level higher than achieved by metal or steroid alone. The effectiveness of steroids at inducing MT was related to their ability to induce a specific glucocorticoid effect, induction of tyrosine aminotransferase. For specific classes of steroids, synthetic glucocorticoids were more potent than the metals in inducing MT, but endogenous glucocorticoids, mineralocorticoids, androgens, and estrogens were less potent than the metals. The concentration of corticosterone, the major endogenous glucocorticoid of rats, required to induce MT in hepatocytes was 100 times higher than concentrations achievable in the plasma of rats. In conclusion, in rat hepatocytes dexamethasone was a more potent but less effective inducer of MT than Zn or Cd; synthetic glucocorticoids were more potent but endogenous adrenalcorticoids (i.e., glucocorticoids, mineralocorticoids, androgens, and estrogens) were both less potent and less effective inducers of MT than were metals, suggesting that glucocorticoids may not be the mediator for stress-induced MT induction; and induction of MT by steroids correlated well with the induction of tyrosine aminotransferase, supporting the involvement of a hormone-receptor complex in the induction of MT by steroids.     

Influence of chemical and environmental stressors on acute cadmium toxicity

Previous investigations have demonstrated that the cytosolic protein metallothionein (MT) is induced not only by exposure to certain heavy metals but also by a variety of other factors, including environmental stress. While MT synthesis has been observed with exposure to cold temperatures, there is a paucity of data concerning the influence of cold on heavy-metal toxicity. The present investigation focused on the influence of metal and cold pretreatments on the acute toxicity of cadmium. Mortalities of 80% and 100% were observed for mice orally administered challenge doses of 100 mg Cd/kg and 150 mg Cd/kg, respectively. To determine a protective cadmium pretreatment dose, animals were administered 2.5, 5, 10, 20, 25, and 50 mg Cd/kg 24 h prior to cadmium challenge. In animals pretreated with 10 mg Cd/kg, mortalities of 20% and 70% were observed with the respective challenge doses. Immediately following cold stress (4 degrees C, 12 h), mortalities of 30% and 90% were observed with cadmium challenge doses of 100 and 150 mg Cd/kg, respectively. Significant correlations were demonstrated between induced hepatic MT concentrations and cadmium pretreatment (r = 0.99), as well as cold pretreatment (r = 0.87). Results of this investigation indicate that stressors, such as cold, influence the acute toxicity of cadmium to the same magnitude as metal pretreatment. This induced tolerance to cadmium was attributed, in part, to the induction of MT synthesis. Furthermore, the induced levels of MT resulting from cold stress may confound the simplistic approach of using MT as a biological monitor of occupational exposure to cadmium.     

Cadmium-induced inhibition of hepatic drug oxidation in the rat: Time dependency of tolerance development and metallothionein synthesis

Experiments were undertaken to determine if a correlation existed between the time-dependent synthesis of hepatic metallothionein and the development of tolerance to the inhibition of hepatic drug oxidation elicited by cadmium in the male rat. Maximal rates of metallothionein synthesis were achieved within 2 hr after administering cadmium in a 0.21 mg Cd/kg (ip) dose. The total hepatic concentration of metallothionein, as well as the cadmium binding capacity of this protein, also increased rapidly with maximal values being observed from 8 to 67 hr after cadmium administration. Despite this rapid increase in hepatic metallothionein levels, the tolerance to the inhibition of in vivo drug oxidation induced by a challenge cadmium (0.84 mg Cd/kg) dose did not develop until 16 hr after treatment with the 0.21 mg/kg cadmium dose. Furthermore, hepatic metallothionein levels decreased from a maximum at 67 hr to approximately control levels at 336 hr. Although the tolerance to the inhibition of drug oxidation also decreased from a maximum at 72 hr a modest degree of protection was maintained even at 336 hr. Pretreatment with the 0.21 mg Cd/kg dose increased the hepatic uptake of a ¹⁰⁹Cd challenge dose (0.84 mg Cd/kg). This increase was associated with an increased ¹⁰⁹Cd binding to metallothionein in the cadmium-pretreated animals. While these data are suggestive of a role for metallothionein in tolerance development, the lack of correlation of the time course of metallothionein synthesis with the development of the tolerance would suggest that factors in addition to metallothionein may also participate.     

Altered subcellular distribution of cadmium following cadmium pretreatment: possible mechanism of tolerance to cadmium-induced lethality

Animals pretreated with cadmium (Cd) subsequently develop tolerance to an otherwise lethal dose of Cd. Possible mechanisms for this tolerance include reduced absorption, an altered tissue distribution, and an altered subcellular distribution of Cd. Male rats received a single Cd pretreatment (2.0 mg/kg, sc) 24 hr prior to administration of a typically lethal challenge dose of Cd (3.9 mg/kg, iv). Tolerance was evident because no mortality was observed in Cd-pretreated rats. Since Cd induces synthesis of hepatic metallothionein (MT), a higher percentage of the challenge dose might be sequestered in the liver of Cd-pretreated animals with less distributed to target organs of toxicity. At 2 and 24 hr following Cd challenge, no marked changes in organ distribution of the challenge dose of Cd were observed as a result of Cd pretreatment. However, isolation of hepatic subcellular fractions 2 hr following injection of the challenge dose revealed less Cd in nuclei, mitochondria, and endoplasmic reticulum, and more in cytosol as a result of Cd pretreatment. The increased cytosolic Cd was bound primarily to MT which had been induced markedly by Cd pretreatment. These data indicate that differences in absorption or tissue distribution of Cd are unlikely explanations for development of tolerance to Cd. Rather, tolerance appears to result from an MT-related change in the hepatic subcellular distribution of Cd, evidenced by lower concentrations of Cd in nuclei, mitochondria, endoplasmic reticulum, and cytosolic high-molecular-weight proteins and higher concentrations bound to MT in cytosol.     

Induction of metallothionein in rat primary hepatocyte cultures: evidence for direct and indirect induction

The ability of a number of metals and organic chemicals to induce metallothionein (MT) synthesis in primary cultures of rat hepatocytes was tested to determine whether MT induction in vivo results from a direct effect of the agent on the liver or as a result of an indirect, physiologic response to the agent. Hepatocytes were exposed to metals [zinc (Zn), cadmium (Cd), mercury (Hg), manganese (Mn), lead (Pb), cobalt (Co), nickel (Ni), and vanadium (V)] or organic compounds [ethanol, urethane, L-2-oxothiozolidine 4-carboxylate (L-OTCA), or dexamethasone] and were assayed for metallothionein by the Cd/hemoglobin radioassay. Cell viability was monitored by protein synthesis activity and cellular K+ concentration. Increases in MT concentrations were noted for Zn (22-fold), Hg (6.4-fold), Cd (4.8-fold), Co (2.4-fold), Ni (2.2-fold), and dexamethasone (4.5-fold). However, even at maximum tolerated concentrations, Mn, Pb, V, ethanol, urethane, and L-OTCA did not increase MT. The results indicate that Zn, Cd, Hg, Co, Ni and dexamethasone induce MT in vitro and thus are direct inducers of MT synthesis in hepatic tissue. In contrast, Mn, Pb, ethanol, urethane and L-OTCA, which did not increase the MT content of hepatocytes, apparently do so in vivo by an indirect mechanism.     

Metallothionein-null mice are more sensitive than wild-type mice to liver injury induced by repeated exposure to cadmium.

Liver is a major target organ of cadmium (Cd) toxicity following acute and chronic exposure. Metallothionein (MT), a low-molecular-weight, cysteine-rich, metal-binding protein has been shown to play an important role in protection against acute Cd-induced liver injury. This study investigates the role of MT in liver injury induced by repeated exposure to Cd. Wild-type and MT-I/II knockout (MT I/II-null) mice were injected sc with a wide range of CdCl(2) doses, 6 times/week, for up to 10 weeks, and their hepatic Cd content, hepatic MT concentration, and liver injury were examined. Repeated administration of CdCl(2) produced acute and nonspecific chronic inflammation in the parenchyma and portal tracts and around central veins. Higher doses produced granulomatous inflammation and proliferating nodules in liver parenchyma. Apoptosis and mitosis occurred concomitantly in liver following repeated Cd exposure, whereas necrosis was mild. As a result, significant elevation of serum enzyme levels was not observed. In wild-type mice, hepatic Cd concentration increased in a dose- and time-dependent manner, reaching 400 microgram/g liver, along with 150-fold increases in hepatic MT concentrations, the latter reaching 1200 microgram/g liver. In contrast, in MT I/II-null mice, hepatic Cd concentrations were about 10 microgram/g liver. Despite the lower accumulation of Cd in livers of MT I/II-null mice, the maximum tolerated dose of Cd was one-eighth lower than that for wild-type mice at 10 weeks, and liver injury was more pronounced in the MT I/II-null mice, as evidenced by increases in liver/body weight ratios and histopathological analyses. In conclusion, these data indicate that (1) nonspecific chronic inflammation, granulomatous inflammation, apoptosis, liver cell regeneration, and presumably, preneoplastic proliferating nodules are major features of liver injury induced by repeated Cd exposure, and (2) intracellular MT is an important protein protecting against this Cd-induced liver injury.     

Tolerance to cadmium hepatotoxicity by metallothionein and zinc: in vivo and in vitro studies with MT-null mice

The protective role of metallothionein (MT) in Cd-mediated hepatotoxicity was investigated in vivo and in vitro. Following injection of Cd (2 mg/kg, intraperitoneal or subcutaneous) hepatoxicity was significantly greater at 20 h in metallothionein-null (MT−/−) mice, compared with controls (MT+/+). The decrease in the blood and liver glucose concentrations correlated with the extent of hepatotoxicity, with blood glucose 43% lower in MT−/− mice. Zinc (50 μM) and/or Dex (1 μM) were used in hepatocyte cultures to raise MT 2–5-fold. When Cd at 10 μM was co-treated with Zn and/or Dex, lactate dehydrogenase (LD) leakage in the MT+/+ and MT−/− hepatocytes was reduced only when Zn was present. Cellular glutathione (GSH) was the same in control MT+/+ and MT−/− cultures and was uninfluenced by Zn and Dex. After treatment with 5 and 10 μM Cd, GSH levels were lower in MT−/− than MT+/+ hepatocytes in the control and Dex groups. Higher GSH concentrations were maintained in Zn co-treated cultures from both genotypes, indicating that the superior protective effect of Zn may in part derive from its influence on cellular GSH. Pre-treatment with Zn and/or Dex provided no further protection than co-treatment. Tolerance to brief (15 min) Cd exposure was also investigated in the presence of MT inducers including progesterone (100 μM). Zn, Dex and progesterone treated hepatocytes had less LD leakage than controls with Zn giving the greatest protection (LD leakage 18% of controls at 100 μM Cd). Zn pre-treated cells had higher cytosolic/particulate ratios of Cd. These findings demonstrate that MT protects primary cultures of mouse hepatocytes from short-term exposure to Cd. Zn enhances the protection through MT and non-MT mechanisms.     

Resistance to cadmium-induced hepatotoxicity in immature rats

Because the concentration of metallothionein (MT) in perinatal rat liver is 10 to 20 times higher than levels present in liver of untreated adult rats, it was of interest to determine if immature rats are less susceptible to the hepatotoxic effects of cadmium (Cd) seen in adults. Male Sprague-Dawley adult rats received a hepatotoxic dose of 4.0 mg Cd/kg, iv, and 10-day-old rats received 4.0, 5.0,or 6.0 mg Cd/kg, iv. Ten hours following Cd injection, plasma enzyme activities in adults were elevated (aspartate aminotransferase, 50-fold; sorbitol dehydrogenase, 87-fold) and histologic examination showed extensive hepatic injury; however, no damage was evident in 10-day-old rats, even at the 6 mg Cd/kg dose. Two hours after injection of 3.5 mg Cd/kg, iv (7 μCi ¹⁰⁹Cd/mg Cd), the concentration of Cd was higher in liver, heart, and brain and lower in kidneys of 10-day-old rats compared to adults. An age comparison of the hepatic subcellular distribution of Cd revealed a higher amount of Cd in cytosol and less in the particulate fraction of 10-day-old rats. Furthermore, cytosolic Cd was predominantly bound to MT. These data support the hypothesis that presynthesized levels of MT are important in producing tolerance to acute Cd toxicity and that tolerance results from an altered hepatic subcellular distribution of Cd.     

Effects of fasting on cadmium toxicity, glutathione metabolism, and metallothionein synthesis in rats

Acute oral toxicity of Cd (as cadmium chloride) was enhanced in rats fasted 24 hr, as shown by a markedly decreased LD50. To examine the relationship among Cd toxicity, hepatic glutathione (GSH), and metallothionein (MT) during fasting, rats were administered 75 mg Cd/kg orally 24 hr after fasting and euthanized after a further 4 or 24 hr for various assays. Serum glutamic-pyruvic transaminase activity 24 hr after Cd treatment was higher in fasted rats than in fed rats. Both total GSH and nonprotein sulfhydryl (NPSH) concentrations in liver decreased to 50% of control levels after 28 hr of fasting and returned to 75% of control values by 48 hr. Total hepatic GSH concentration in fed rats decreased 4 and 24 hr after Cd treatment, whereas that in fasted rats remained unchanged at 4 hr and decreased significantly at 24 hr. Cd uptake by the liver (both concentration and content) 24 hr after Cd treatment was higher in fasted rats than in fed rats. Hepatic MT concentration was markedly increased by Cd treatment and higher in fasted rats than in fed rats. There was no relationship between Cd toxicity and hepatic thiobarbituric acid (TBA) value, an indicator of lipid peroxidation. Fasting had no effect on hepatic GSH peroxidase and GSH reductase activities. These enzymes probably are not involved in Cd toxicity. On histological examination, focal degenerative and necrotic changes were observed from the midlobular to the pericentral region in the livers of fed rats 24 hr after Cd treatment. These changes were enhanced by fasting, diffusing from the pericentral to the periportal region. Histochemical examination revealed a heterogeneous distribution of GSH in the livers of fed rats, with strong staining of GSH in the periportal region. This heterogeneous distribution of GSH in liver was not observed in fed rats 4 hr after Cd treatment or in fasted rats at 24 hr. The present results suggest that hepatic GSH plays an important role in protection against Cd toxicity before the onset of MT synthesis. Animals in bad condition, such as that resulting from interruption of nutrient supply, cannot be protected against Cd toxicity even if the hepatic MT level is high.     

Endotoxin induction of hepatic metallothionein is mediated through cytokines

Metallothionein (MT), a low molecular-weight, cysteine-rich, metal-binding protein, is induced by many environmental factors and a variety of stimuli. Bacterial endotoxin (lipopolysaccharide, LPS) injection is experimentally used to produce acute stress and is an effective inducer of hepatic MT. However, the mechanism of LPS induction of MT is not known. In the present studies, we used two substrains of mice, differing in their production of cytokines after LPS administration, to test the hypothesis that MT induction by LPS is mediated through cytokines. Normal (C3Heb/FeJ) and low cytokine-producing (C3H/HeJ) mice were given various doses of LPS, interleukin-1 (IL-1), interleukin-6 (IL-6), or tumor necrosis factor (TNF), and hepatic MT was determined 24 hr later by the Cd/hemoglobin assay. The low-cytokine-producing mice were much less responsive to the induction of MT by LPS (50 vs 150 micrograms MT/g liver after 1.0 mg LPS/kg, ip) than the normal mice, but were equally responsive to the induction of MT by IL-1 (0.03-1.0 microgram/mouse). IL-6 (0.5-5.0 micrograms/mouse), and TNF (0.005-0.5 microgram/mouse). All the cytokines produced a dose-dependent increase of hepatic MT levels in these two murine substrains (up to five- to sevenfold over controls). In conclusion, these data suggest that LPS induction of MT may be mediated through cytokines.     

钙和镉对金属硫蛋白在小鼠肝合成中的影响

研究了小鼠经口给于钙盐和镉盐后，钙和镉在小鼠肝金属硫蛋白合成中的相互影响。结果发现：单独给于钢（８ｍｇ／ｋｇ）时，镉能诱导肝金属硫蛋白的合成；单独给于钙（２０ｍｇ／ｋｇ）时，肝ＭＴ的含量无明显的增加；但同时经口给于钙和镉（２０＋８ｍｇ／ｋｇ），则肝ＭＴ含量比单独给于镉时的肝ＭＴ含量明显增加（Ｐ＜０．０５），Ｃａ＋Ｃｄ组的肝Ｚｎ浓度大大高于Ｃｄ组。     

Differential modulation of lipopolysaccharide- and zymosan-induced hypophagia by dexamethasone treatment

The treatment of experimental animals with lipopolysaccharide (LPS) induces behavioral depression, in which the central and peripheral inductions of proinflammatory cytokines are proposed to play an important role. We have shown that the intraperitoneal injection of zymosan, composed of insoluble particles prepared from yeast cell walls, can induce behavioral depression assessed as hypophagia in mice, although the role of proinflammatory cytokines in this response has not yet been investigated. We have also shown that the subcutaneous injection of the corticoid, dexamethasone (Dex), a potent inhibitor of cytokine production, is effective in attenuating hypophagia in LPS-treated mice. The attenuated response was associated with the suppression of the gene induction of proinflammatory cytokines (i.e., IL-1beta, IL-6 and TNFalpha) in the brain and liver. In contrast, no significant induction of proinflammatory cytokine genes was observed in the brain or liver during zymosan-induced hypophagia; the subcutaneous injection of Dex did not attenuate zymosan-induced hypophagia but its intraperitoneal injection did. Thus, zymosan-induced hypophagia was less responsive to a subcutaneous injection of dexamethasone than LPS-induced hypophagia, which may be due to the limited role of systemic inflammation in this response. An important role of localized, rather than systemic, inflammation in zymosan-induced hypophagia was suggested, although the role of local proinflammatory cytokines remains to be clarified.     

Involvement of oxidative stress in the synthesis of metallothionein induced by mitochondrial inhibitors

We previously reported that synthesis of metallothionein (MT) was induced by mitochondrial inhibitors such as 2,4-dinitrophenol (DNP) or antimycin A (Kondoh et al., 2001), which are potent inhibitors of mitochondrial respiration. Although the inhibitors are known to be radical generators in mitochondria, the involvement of oxidative stress in the synthesis of MT induced by mitochondrial inhibitors and the biological functions of MT remain obscure. In this study, therefore, we examined the involvement of oxidative stress in MT synthesis induced by mitochondrial inhibitors and the biological functions of MT. In cultured mouse fibroblast cells, the addition of DNP increased both MT concentration and MT mRNA level. Administration of DNP to L-buthionine-SR-sulfoximine (BSO)-pretreated mice increased hepatic lipid peroxidation and induction of MT synthesis. In addition, vitamin E prevented induction of MT synthesis as well as lipid peroxidation in the liver of mice caused by administration of DNP. Administration of mitochondrial inhibitor to mice elevated the levels of lipid peroxidation in the liver and mitochondria, and MT in the liver, indicating the generation of mitochondrial oxidative stress. These data suggest that the induction of MT synthesis by mitochondrial inhibitors is correlated with generation of oxidative stress in mitochondria. Furthermore, the level of DNP-induced alanine aminotransferase (ALT) activity, reflecting hepatic damage, was greater in MT-null mice than in wild-type mice, and intracellular accumulation of reactive oxygen species (ROS) caused by the action of mitochondrial inhibitors was greater in MT-null fibloblast cells than in wild-type cells. The results suggest that MT plays a role as a radical scavenger of intracellular ROS produced in mitochondria. Taken together, the results suggest that mitochondrial oxidative stress induces the synthesis of MT, which may contribute to regulation of mitochondrial ROS production.     

Induction of hepatic metallothionein by nonmetallic compounds associated with acute-phase response in inflammation.

Induction of hepatic metallothionein (MT) synthesis by several nonmetallic compounds and its relationship to an acute-phase response in inflammation were studied in mice. Subcutaneous injections of menadione, paraquat, carbon tetrachloride (CCl4), and several organic solvents caused an increase of hepatic MT concentration. This MT contained only zinc. Menadione and n-hexane caused the greatest accumulation of hepatic MT among these nonmetallic compounds (about 13-fold). The concentration of Zn was significantly decreased in plasma in contrast to liver after an injection of these nonmetallic compounds. When 65ZnCl2 was injected iv after these injections, uptake of 65Zn to the liver was increased. This effect was not observed after treatment with cycloheximide. The association with inflammation of this induction of MT accumulation was examined by determination of acute-phase proteins. The concentration of fibrinogen in the plasma was significantly increased following injection of those nonmetallic compounds which caused marked hepatic MT accumulation. An injection of 1 N NaOH, 1 N HCl, turpentine oil, or endotoxin caused a significant increase in the plasma concentration of fibrinogen and in the hepatic MT concentration. Injections of n-hexane as well as turpentine oil significantly increased hepatic MT concentration and plasma concentration of fibrinogen and ceruloplasmin with time. The concentration of fibrinogen was significantly correlated (r = 0.789) with the concentration of hepatic MT. Neither adrenalectomy nor pretreatment with dexamethasone prevented hepatic MT accumulation caused by these compounds. These results indicate that induction of hepatic MT synthesis by these nonmetallic compounds is associated with an acute-phase response in inflammation and is independent of glucocorticoids.