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In the adult liver, drug-metabolizing enzymes such as cytochrome P450 (CYP) efficiently metabolize drugs by forming an expression pattern called "zonation" structure around the central veins (CV). However, most previous studies on CYPs have focused on the expression levels of CYP mRNA and proteins in the whole liver. In this study, we analyzed not only the expression levels of Cyp2c family mRNAs and proteins in mice during fetal liver development, but also the relationship with their localization. In the whole fetal liver, Cyp2c mRNA and protein were hardly expressed. On the other hand, zonation analysis results showed that only some cells around the CV of the fetal liver expressed Cyp2c. In addition, the protein expression level of Cyp2c in the whole liver during the neonatal period started from postnatal day (P) 7 in both males and females, while the zonation was weakly formed from P5. This study suggested that fetal liver cannot metabolize Cyp2c substrate drugs transferred from mother to fetus due to the low expression of Cyp2c and unformed zonation. The expression level of Cyp2c protein in neonates was lower than that in adult liver, and the zonation structure was not clear, suggesting that drug metabolism was not sufficient. Furthermore, this study revealed that the expression level of Cyp2c does not correlate with the formation of zonation structures, because Cyp2c expression is found in hepatocytes near the CV even in the fetal and neonatal stages, when Cyp2c protein expression is hardly detectable in the whole liver., (© 2022 John Wiley & Sons Ltd.)

Background: Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Kupffer cells play a central role in promoting hepatic inflammation, which leads to the development of NASH. We investigated the anti-inflammatory effect of hepatic vagus-mediated stimulation of the α7 nicotinic acetylcholine receptor (α7nAChR) on Kupffer cells in NASH pathogenesis., Methods: Wild-type (WT) mice undergoing hepatic vagotomy (HV) were fed a methionine- and choline-deficient (MCD) diet for 1 week. α7nAChR knockout (α7KO) chimeric mice were generated by transplanting α7KO bone marrow cells into irradiated and Kupffer cell-deleted WT recipients. Kupffer cells were isolated from WT mice and treated with α7nAChR agonist under stimulation by lipopolysaccharide and/or palmitic acid., Results: HV aggravated MCD diet-induced NASH in both steatosis and inflammation. The hepatic inflammatory response, including the upregulation of tumor necrosis factor alpha (TNFα), interleukin (IL)-12, and monocyte chemoattractant protein 1 (MCP-1), was accelerated in HV mice, accompanied by the downregulation of PPARα pathway genes. Kupffer cells were highly activated via the phosphorylation and nuclear translocation of nuclear factor-kappa B (NF-κB) in MCD diet-fed HV mice. The α7nAchR agonist suppressed the inflammatory response of primary Kupffer cells induced by lipopolysaccharide and palmitic acid by attenuating the NF-κB cascade. α7KO chimeric mice fed an MCD diet for 1 week developed advanced NASH with highly activated Kupffer cells. The hepatic expression of TNFα, IL-12, and MCP-1 was upregulated in α7KO chimeric mice, accompanied by abnormal lipid metabolism., Conclusions: Hepatic vagus activity regulates the inflammatory response of Kupffer cells via α7nAChR in NASH development.

Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in the United States. Hepatocyte steatosis is a component of metabolic syndrome and insulin resistance. Hepatic steatosis may be benign or progress to hepatocyte injury and the initiation of inflammation, which activates immune cells. While Kupffer cells are the resident macrophage in the liver, inflammatory cells such as infiltrating macrophages, T lymphocytes, neutrophils, and DCs all contribute to liver inflammation. The inflammatory cells activate hepatic stellate cells, which are the major source of myofibroblasts in the liver. Here we review the initiation of inflammation in the liver, the liver inflammatory cells, and their crosstalk with myofibroblasts., Competing Interests: The authors have declared that no conflict of interest exists.

Liver fibrosis results from chronic injury of hepatocytes and activation of Collagen Type I producing myofibroblasts that produce fibrous scar in liver fibrosis. Myofibroblasts are not present in the normal liver but rapidly appear early in experimental and clinical liver injury. The origin of the myofibroblast in liver fibrosis is still unresolved. The possibilities include activation of liver resident cells including portal fibroblasts, hepatic stellate cells, mesenchymal progenitor cells, and fibrocytes recruited from the bone marrow. It is considered that hepatic stellate cells and portal fibroblasts are the major source of hepatic myofibroblasts. In fact, the origin of myofibroblasts differs significantly for chronic liver diseases of different etiologies, such as cholestatic liver disease or hepatotoxic liver disease. Depending on etiology of hepatic injury, the fibrogenic foci might initiate within the hepatic lobule as seen in chronic hepatitis, or primarily affect the portal areas as in most biliary diseases. It has been suggested that activated portal fibroblasts/myofibroblasts work as "myofibroblasts for cholangiocytes" while hepatic stellate cells work as "myofibroblast for hepatocytes". This review will focus on our current understanding of the activated portal fibroblasts/myofibroblasts in cholestatic liver fibrosis., (Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10 months old) and old (20 months old) aged, male C57BL/6N mice were fed either a low-fat diet (4 % fat) or HFD (60 % fat) for 4 months. Young (3 months old) aged mice were included as control group. HFD-induced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-α, IL-1β, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-α1, αSMA, TGF-β1, TGF-β2, TGFβRII, PDGF, PDGFRβII, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between old-aged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or fibrosis, while the differential effect of aging on HFD-induced renal injury was not remarkable as shown in the liver., Competing Interests: None. Financial support and sponsorship This research was supported by The GlaxoSmithKline Research Fund of the Korean Association for the study of the Liver (In Hee Kim). Support: NIH R01MH094151-01 and MH019934, and the Sam and Rose Stein Institute for Research on Aging, University of California, San Diego.

Optical imaging is unique among in vivo imaging methods because it is possible to simultaneously resolve two or more probes emitting at different wavelengths of light. We employed two near-infrared (NIR) fluorescent optical probes, each labeled with a different protein, to simultaneously evaluate the pharmacokinetics of each probe. Dynamic optical imaging was performed in live mice after the coinjection of bovine serum albumin (BSA) and galactosamine-conjugated bovine serum albumin (GmSA) labeled with either Cy5.5 or Cy7 NIR dyes. The pharmacokinetics of BSA and GmSA were independently and simultaneously visualized. Next, two-color dynamic imaging of biotinylated BSA (b-BSA) and BSA labeled with Cy5.5 or Cy7 was performed before and after an avidin "chase." Following avidin injection, fluorescently labeled b-BSA rapidly accumulated in the liver, while minimal liver uptake of BSA was noted. Thus, multicolor dynamic contrast-enhanced optical imaging can be performed to noninvasively track the pharmacokinetics of different proteins. This imaging technique can be applied to a wide variety of optically labeled proteins in order to simultaneously track their biodistribution.

Previously, we reported that the oral administration of green tea rich in catechins restored levels of several biomarkers increasing in galactosamine-treated rats to nearly control values. These biomarkers included serum transaminase activities, serum concentrations of tumor necrosis factor-alpha and interleukin 1-beta, and the hepatic mRNA expression of these inflammatory cytokines. In the present study, we examined possible anti-fibrotic effects of green tea in galactosamine-induced hepatitis. The results of the reverse transcription and polymerase chain reaction indicated that the increase in gene expression of the alpha1 chain of collagen type 1 and transforming growth factor beta-1 in the injured liver 24 h post-injection of galactosamine was suppressed by the administration of green tea. Masson's trichrome staining demonstrated that the extent of fibrogenesis after 14 days was greater in the galactosamine-injured livers not treated with green tea than the treated ones. These results suggest that the drinking of green tea with a high catechin content may help to prevent and/or attenuate the development of fibrosis in hepatitis.

Galactosamine is known to induce hepatic injury in rats and the galactosamine-induced hepatitis is believed to be similar to viral hepatitis both morphologically and functionally. In the present study, we examined how drinking green tea affects the gene expression of inflammatory cytokines which may be up-regulated in galactosamine-induced hepatitis. As has been reported, galactosamine caused hepatic injury in rats as evidenced by an increase in serum transaminase activities and histological observations of the liver. The results of the reverse transcription and polymerase chain reaction indicated an increased gene expression of inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, in the injured liver and the enzyme linked immunoassay showed an increase in the serum levels of these cytokines. Oral administration of green tea rich in catechins (Healthya green tea) restored these biomarkers in the galacotsamine-treated rats to near the control levels. These results suggest that the drinking of green tea with a high catechin content may help to prevent and/or attenuate the development of a certain type of hepatitis.

It has recently been reported that the major green tea polyphenolic constituent, epigallocatechin 3-gallate (EGCG), mimics the cellular effects of insulin including the reductive effect on the gene expression of rate-limiting gluconeogenic enzymes in a cell culture system. We show that administration of green tea that contains EGCG caused a reduction in the level of mRNAs for gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the mouse liver. EGCG alone was also found to down-regulate the gene expression of these enzymes but not so curcumin or quercetin. The results of this study support the idea that green tea intake may be beneficial in the prevention of diabetes mellitus.

Serum alpha-fetoprotein (AFP) levels in hepatocellular carcinoma (HCC) patients and expression of the protein in cultured HCC cell lines are highly variable. These observations may arise from features correlated with tissue-specific expression of the gene. Extremely strong and potent liver-specific enhancer activity is confined from -4.1 to -3.3 kb upstream to the human AFP gene in contrast with that of the rodent which exists in three widely separated regions. To understand the tissue-specific expression of AFP, we examined cis-acting elements in the enhancer. Results revealed binding sites for selected liver-enriched transcription factors (LETFs) in both domains A (-4120 to -3756 bp) and B (-3492 to -3300 bp) of the gene. These sites included: one hepatocyte nuclear factor (HNF)-1 and HNF-4, two HNF-3, and two C/EBP binding sites in domain A. An adjacent domain B contained one HNF-3 site and three C/EBP sites plus a previously identified HNF-1 site. Each of these elements alone has the ability to stimulate heterogeneous promoter activity in a dose-dependent manner when transfected into AFP producing cells. A comparative study showed that the presence of two HNF-1 and one HNF-4 site is a characteristic feature of human but not rodent AFP enhancer. The mRNA levels of the liver-enriched transcription factors (LETFs) were variable in individual HCC cell lines and together with silencer activities may underlie differential expression of the AFP gene.

To explore the possibility of using catalase for the treatment of reactive oxygen species (ROS)-mediated injuries, the pharmacokinetics of bovine liver catalase (CAT) labeled with 111In was investigated in mice. At a dose of 0.1 mg/kg, more than 70% of 111In-CAT was recovered in the liver within 10 min after intravenous injection. In addition, 111In-CAT was predominantly recovered from the parenchymal cells (PC) in the liver. Increasing the dose retarded the hepatic uptake of 111In-CAT, suggesting saturation of the uptake process. This cell-specific uptake could not be inhibited by coadministration of various compounds which are known to be taken up by liver PC, indicating that the uptake mechanism of CAT by PC is very specific to this compound. The preventive effect of CAT on a hepatic ischemia/reperfusion injury was examined in mice by measuring the GOT and GPT levels in plasma. A bolus injection of CAT at 5 min prior to the reperfusion attenuated the increase in the levels of these indicators in a dose-dependent manner. These results suggest that catalase can be used for various hepatic injuries caused by ROS.

The phenotypes of infiltrating lymphocytes in liver with chronic hepatitis C, including changes associated with interferon (IFN) treatment, were characterized. Specimens obtained from 22 patients treated with IFN were examined using avidin-biotin-peroxidase immunohistochemistry. In areas of lobular and periportal inflammation, most lymphocytes were CD8+ T cells of the CD45RO+ (memory) subset. The centres of lymphoid follicles were occupied by CD20+ B cells and a few CD4+ T cells which were CD45RA+ (naive subset). Follicular centres were surrounded mainly with CD4+ T cells. CD8+ T cells, mostly CD45RO+, were scattered through the mantle zones of follicles and extended around them. No significant changes in CD45RA+ lobular infiltrates accompanied IFN treatment. On the other hand, the number of CD45RO+ lobular infiltrates decreased after IFN treatment in complete responders (P < 0.01). Moreover, there were significant correlations between CD45RO+ cell counts and serum alanine aminotransferase concentrations, CD45RO+ cell counts and the liver histologic grade and CD45RO+ cell counts and CD8+ cell counts. These results suggest that CD8+ memory T cells participate in hepatocyte injury in chronic hepatitis C, and that a decrease of CD8+ memory T cells correlates with the decreased liver inflammation with IFN treatment.

To demonstrate noradrenaline-immunoreactive nerve fibres in liver tissues, we used an antibody to noradrenaline in the immunostaining of liver tissues from rats, guinea-pigs and humans. The tissue specimens were fixed by perfusion or immersion with cacodylate buffer containing sodium metabisulphate and glutaraldehyde, and cryostat sections were prepared. An indirect peroxidase-labelled antibody method was used for staining noradrenaline. Noradrenaline-immunoreactive nerve fibres were localized around blood vessels in the portal area and around the central vein. There were differences between the species in the intralobular distribution of noradrenaline-immunoreactive fibres. Normal guinea-pig and human liver showed intralobular noradrenaline-immunoreactive fibres while rat liver did not. Noradrenaline-immunoreactive fibres were absent from regenerating nodules in a human cirrhotic liver. This method of demonstrating noradrenaline directly using perfusion- or immersion-fixation is appropriate for studying innervation in normal and damaged livers of various species including humans.

Small liver cancer is defined as a solitary hepatocellular carcinoma (HCC) with a diameter less than 2cm. To detect liver cancer as early as possible, patients with liver cirrhosis are screened by ultrasound scanning. Pathological diagnosis in needle aspiration biopsy materials is needed because of low positivity of imaging other than ultrasound scanning. Pathological features are different from those of classical hepatocellular carcinoma. Most of the small HCCs are characterized by the following features: (1) increased cellularity, (2) increased nucleus/cytoplasm ratio, (3) irregular thin trabecular pattern, (4) pseudoglandular or acinar structures, (5) increased staining affinity (eosinophilic/basophilic), (6) frequent fatty change, and (7) residue of the portal tract. Capsules of HCCs, 1-1.5 cm in diameter, are formed. Before the formation of capsules, cancerous cells show a replacing growth pattern. Two cases of small HCC are presented, and these characteristic features are explained.

We have cloned the cDNA of the rat liver 13k protein, that has glutathione binding activity, from a rat liver cDNA library. The nucleotide sequence of this cDNA predicts a protein of 115 amino acids. This protein has 99.1%, 89.6% and 73.0% homology with mouse, human and chicken macrophage migration inhibitory factor (MIF), respectively. This indicates that the rat liver 13k protein is homologue of the MIF. The N-terminal 25 amino acids show 35% sequence similarity with that of the rat glutathione transferase Yb subunit. Although the remaining C-terminal sequence has no sequence identity with glutathione transferase Yb subunit, about 50% homology was found, if conservative substitutions and gaps were taken into account. Northern blot analysis indicates that this gene is expressed in a wide variety of organs including brain, spleen, liver, muscle and kidney. Southern blot analysis suggests that the MIF gene has many pseudo-genes or/and closely related genes.

The distribution of synaptophysin, specifically located in nerve terminals, was investigated immunohistochemically in normal and diseased human livers in 4 patients with normal liver, 6 with chronic active hepatitis, 12 with cirrhosis, and 8 with hepatocellular carcinoma. In normal liver and chronic hepatitis synaptophysin immunoreactivity was detected in the lobules and portal areas. In cirrhosis it was found in the fibrous septum but in no pseudolobules. Parenchymal innervation would thus appear to cease with the development of cirrhosis, and denervation from the parenchyma may lead to various functional abnormalities in liver cirrhosis. In hepatocellular carcinoma no synaptophysin immunoreactivity was found along carcinomatous sinusoids. Immunoreactive spots were present in the capsules of hepatocellular carcinoma to a much lesser extent than in the fibrous septum of cirrhosis. Neural functions may thus have little effect on the microcirculation of hepatocellular carcinoma.

Liver biopsy specimens with or without liver diseases were examined immunohistochemically to determine the distribution of endothelial cell markers, factor VIII-related antigen (FVIII-RAg). Ulex europaeus agglutinin I (UEA-I) lectin and PAL-E. We also investigated the localization of laminin, a component of the basement membrane. In normal livers, FVIII-RAg, UEA-I and laminin were negative in sinusoidal endothelial cells, but positive in blood vascular endothelia of the portal area. The antigen detected by PAL-E was distributed in venous endothelial cells. PAL-E did not label endothelial cells of the artery. In the lobule, immunoreactivity with PAL-E was weakly detected only in some sinusoids of the periportal area. In chronic active hepatitis and liver cirrhosis, FVIII-RAg and UEA-I stained endothelial cells of neovasculatures in the enlarged portal areas of the fibrous septum surrounding pseudolobules. Some sinusoidal endothelial cells in cirrhotic livers were reactive to UEA-I and FVIII-RAg, whereas PAL-E-positive cells were found rarely in the pseudolobules. In carcinomatous sinusoidal endothelial cells, FVIII-RAg, UEA-I and PAL-E were strongly stained. Laminin underlay these carcinomatous sinusoids. These suggest capillarization of sinusoids in hepatocellular carcinoma. The histochemical approach using endothelial cell markers could be a practical tool in the diagnosis of hepatocellular carcinoma.

The localization of tissue inhibitor of metalloproteinases (TIMP) in normal and pathological livers was examined by immunohistochemistry using monoclonal antibodies at the light microscopic level. In normal liver, immunoreactive TIMP was detected in smooth muscle cells and endothelial cells of blood vessels, fibroblasts, bile duct cells and Kupffer cells, indicating that TIMP is likely to be a general element of the liver. Immunoreactivity was observed in newly-formed blood vessels, proliferating bile ductules, and fibroblasts in the expanded portal area and fibrous septa of chronic active hepatitis and cirrhosis. TIMP was strongly stained in the capsule of hepatocellular carcinoma. The intensity of the immunoreaction in the capsule was generally greater than that in cirrhotic liver apart from the tumor mass. In three of five cases with hepatocellular carcinoma, endothelial walls in contact with tumor cells were positive.

In order to elucidate the role of histamine in the liver, we studied the effect of a histamine H1-receptor antagonist on the carbohydrate and lipid metabolism in the rat liver. The administration of the H1-receptor antagonist decreased significantly the contents of glycogen and malonyl-CoA in the liver. However, it did not affect the levels of serum glucose and free fatty acid. These results suggest that histamine may play a part in the regulation of metabolism of carbohydrates and lipids in the liver.

Gas chromatography with electron-capture detection was used to quantify the glucuronic acid conjugate of trichloroethanol, urochloralic acid. The conjugate was extracted into ethyl acetate--ethanol (19:1, v/v) under acidic conditions, and analyzed as its trifluoroacetylated methyl ester or as its acetylated methyl ester. As little as 0.2 microgram of the conjugate was quantified, and the method was applicable to urine, plasma and liver. The synthesis of urochloralic acid from trichloroethanol by rat liver microsomal fraction was demonstrated in the presence of uridine diphosphoglucuronic acid as coenzyme.

Rats were fed various test diets only on the day before sacrifice or every day for 3 weeks prior to sacrifice in order to assess the effects of protein (casein), fat (a mixture of olive and corn oils) and carbohydrate (sucrose) on the liver mixed-function oxidase activity. The activity was determined by measuring metabolic rates of 8 volatile hydrocarbons, i.e., benzene, toluene, styrene, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, and trichloroethylene. Contrary to the general belief, it was found that carbohydrate, not protein or fat, regulates the metabolism of these hydrocarbons: a diet which was deficient in carbohydrate remarkably enhanced the metabolism irrespective of protein and fat contents in the diet. This conclusion was confirmed by employing two types of diet, one in which the carbohydrate was replaced by an isocaloric amount of protein or fat (thus keeping total calories of each diet constant) and the other in which the carbohydrate content was varied with protein and fat contents fixed (total calories of each diet differed from others according to the carbohydrate content). In accordance with this, dietary carbohydrate intake also exerted a remarkable influence on the hepatotoxicity of carbon tetrachloride which needs to be metabolically activated to become cytotoxic: the smaller the intake, the more severe the liver injury.

The activities of liver drug-metabolising enzymes for 16 aromatic or chlorinated hydrocarbons were measured in male rats after a three-week daily intake of ethanol amounting to 30% of total energy intake. Although the ethanol feeding produced only a slight increase in the microsomal cytochrome P-450 content, it increased the in-vitro metabolism of most hydrocarbons three-to six-fold. That a major part of this enhanced activity disappeared after one-day withdrawal of ethanol suggests that recent intake of ethanol plays an important part in accelerating the metabolism of hydrocarbons. The enzyme activity enhanced by ethanol was found to be related with changes occurring not in the soluble but in the microsomal fractions. A metabolism study using toluene as a model substrate indicated that chronic ethanol consumption increases the in-vivo metabolism of this hydrocarbon in rats.

Liver biopsy specimens with or without chronic liver diseases were examined immunohistochemically to determine the distribution of enolase isozymes (alpha, beta, and gamma). In normal liver, alpha-enolase was positively stained in almost all hepatocytes and bile duct cells. beta- and gamma-enolases were localized in hepatocytes and bile duct cells, respectively. Electron microscopic studies revealed that Kupffer cells and sinusoidal endothelial cells had both alpha- and gamma-enolases. In chronic active hepatitis and cirrhosis, proliferated biliary ductular cells had both alpha- and gamma-enolases, but did not express beta-enolase. This is almost the same localization pattern of enolase isozymes as in preexisting bile duct cells. gamma-Enolase was detected in some hepatocytes in eight of 12 cases with chronic active hepatitis and six of 12 cases with cirrhosis. These hepatocytes were small, showed a cobblestone pattern, and binucleate cells were frequent. On the other hand, rosette-formed hepatocytes adjacent to a regenerating bulging lobule were not stained for gamma-enolase. These results suggest that regenerating hepatocytes have gamma-enolase and that, with maturation, hepatocytes lose it.

Innervation of the liver with or without chronic liver disease was immunohistochemically studied. In normal liver tissues, gamma-enolase [neuron-specific enolase (NSE)]- and S-100 protein (S-100)-positive nerve fibers were found around hepatic arteries, portal veins, and bile ductules in the portal area, along the sinusoid, and around central veins inside the hepatic lobule. Neuropeptide Y (NPY)-immunoreactive (IR) nerve fibers were detected in close contact with hepatic arteries and portal veins in the portal area and along the sinusoid in the parenchyma. Vasoactive intestinal polypeptide (VIP)-IR nerve fibers were found in the portal area but were scarce in the parenchyma. VIP-IR nerve fibers were much fewer than NPY-IR fibers. In patients with chronic active hepatitis, NSE- and S-100-positive nerve fibers, as well as NPY-IR nerve fibers, proliferated in the enlarged portal area. In cirrhotic liver, NSE- and S-100-positive nerve fibers and NPY-IR fibers increased remarkably in the fibrous septa, whereas they decreased or vanished inside the pseudolobules. These findings suggest that, in chronic liver disease, intrahepatic nerve fibers change their distribution, accompanying the structural changes in the hepatic lobules.

The effect of a series of trihalomethanes, CHCl3, CHBrCl2, CHBr2Cl, and CHBr3, on in vitro lipid metabolism was compared using rat liver slices. The incorporation of 32Pi and [3H]glycerol into phospholipid of liver slices was inhibited in the presence of trihalomethanes. The inhibitory effect followed the number of bromine atoms in the trihalomethane molecule in the initial period of incubation. CHBr3 markedly inhibited the incorporation of [3H]glycerol into triacylglycerol (TG); CHBr2Cl was less effective and the other two trihalomethanes were without effect. The activities of glycerophosphate acyltransferase, phosphatidate phosphatase and diacylglycerol acyltransferase were changed by the exposure to trihalomethanes. The effects of CHBr2Cl and CHBr3 were much more severe as compared to those of CHBrCl2 and CHCl3. The change in the enzyme activities could explain the alteration in the incorporation of [3H]glycerol into TG.

Metabolic rates of eight hydrocarbons (benzene, toluene, styrene, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, and trichloroethylene) were measured in vitro with the livers from rats that had consumed ethanol for 3 weeks in combination with various diets. Ethanol and carbohydrate antagonized each other in connection with activity of hepatic drug-metabolizing enzymes (mixed-function oxidases); the former increased and the latter decreased these enzymes. A decrease (increase) in carbohydrate intake augmented (suppressed) the action of ethanol in a dose-related manner. In particular, a combination of ethanol with a low-carbohydrate diet (DeCarli and Lieber diet) enhanced enzyme activity and potentiated carbon tetrachloride-induced hepatotoxicity. Enhancement of metabolism and potentiation of toxicity were due to the combination rather than to ethanol per se.

Studies were made with male Wistar rats on the effects of 50% food restriction on the metabolism of eight organic solvents (chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, trichloroethylene, benzene, toluene and styrene) and on the hepatotoxicity induced by carbon tetrachloride inhalation at 400 ppm for 4 h. The activities of liver drug-metabolizing enzymes for these solvents were enhanced almost equally without exception by one-day food restriction, although the restriction produced no significant increase in the microsomal protein and cytochrome P-450 contents. Carbon tetrachloride hepatotoxicity was enhanced by the food restriction, as evidenced by a marked increase of serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) activities in the food-restricted rats. Histological findings of the liver also supported this finding. Thus, food restriction enhances metabolism of organic solvents in the liver, and can modify toxicity of some chemicals such as carbon tetrachloride, which need metabolic activation to become cytotoxic.

The binding sites for [3H]pyrilamine in isolated rat hepatocytes were characterized. Scatchard analysis revealed two kinds of binding sites in hepatocytes, a high-affinity site and a low-affinity one. The rates of binding of the radioligand with the high-affinity binding site and its dissociation were rapid. The specificity of the sites for various histamine antagonists indicated that the high-affinity [3H]pyrilamine binding site is representative of the histamine H1 receptor. Treatment of hepatocytes with protease or phospholipase A2 significantly decreased the maximum binding capacity of the high-affinity site without affecting its dissociation constant, suggesting that the binding site is proteinaceous and is sensitive to a change in the lipid moiety of the membrane. Hepatocytic cyclic AMP and cyclic GMP were not significantly modulated by incubating hepatocytes with histamine. Thus, the action of histamine on hepatocytes might not be mediated by the cyclic nucleotides.

Concentrations of heavy metals (Fe, Mn, Zn, Cu, Pb, Ni, Cd, Co, and Hg) were determined in the muscle, liver, and kidney of 42 Caspian seals and fishes collected from the Caspian Sea in 1993. Higher Mn and lower Fe and Cu concentrations were found in the liver in comparison with other marine pinnipeds. Lower Cu concentrations in the liver appear to be a common feature in small seals belonging to subgenus Pusa, which include ringed, Baikal, and Caspian seals. However, low Fe and high Mn in livers were specific to Caspian seal. Concentrations of toxic metals such as Hg and Cd were relatively low. Pinniped species can be divided into two groups, based on accumulations of Cd or Hg in the liver. Interestingly, it was found that Cd-accumulating groups feed on invertebrates, whereas the preferred diet of Hg accumulators is fish. Caspian seals seemed to belong to the Hg-accumulating group. Cd and Hg concentrations in the liver and kidney of young animals increased with age. Mercury concentrations in adult animals increased with age continuously, whereas Cd concentrations in adult animals decreased. This trend might be due to preferential feeding habits and shift in ratio of Hg and Cd in the diet (i.e., invertebrates to fish). [ABSTRACT FROM AUTHOR]