Hepatic Aminotransferase Activity Research Articles

Effects of fenofibrate on plasma and hepatic transaminase activities and hepatic transaminase gene expression in rats

Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are widely used as sensitive markers of possible tissue damage, particularly liver toxicity. Lipid-lowering drugs, such as fibrates, slightly increase serum transaminase levels in humans, but there is little evidence that the phenomenon is related to drug-induced liver injury (DILI). Some in vitro studies have indicated that the elevations of serum transaminase activities after treatment of humans with fenofibrate, one of the fibrates, are related to increased transaminase synthesis in the hepatocytes rather than to transaminase leakage from the hepatocytes associated with cell lysis. In this study, male F344/DuCrlCrlj (Fischer) rats were treated once with fenofibrate at a dose level of 400 mg/kg and the relationships between the pharmacological effects, blood and hepatic transaminase activities and the gene expression of the transaminases in the liver were investigated. Fenofibrate treatment slightly increased plasma transaminase activities in rats with the findings directly related to the pharmacological action of the drug. The increases were in parallel with increases in hepatic transaminase activities associated with increases in the transaminase genes in the liver and were not considered to be a consequence of hepatotoxicity from the drug. The modification in transaminase gene expression is likely to be secondary to the pharmacological action of fenofibrate. The evidence obtained in our study underlines the importance of gene regulation as a possible alternative mechanism for increased blood transaminase activities.

The safety of dirlotapide in dogs

The safety of dirlotapide in dogs was evaluated in two studies with parallel designs. In an acute tolerance study, 24 beagles (six dogs per treatment) were treated orally once daily for 14 days with placebo or dirlotapide at 2.5, 5.0, or 10.0 mg/kg/day. In a margin-of-safety study, 38 overweight, neutered beagles were treated orally once daily for 3 months with dirlotapide at doses up to 0.5 mg/kg/day (six dogs), 1.5 mg/kg/day (12 dogs) and 2.5 mg/kg/day (six dogs). Control dogs received placebo at 0.3 mL/kg/day (10 dogs) and 0.5 mL/kg/day (four dogs). Results were similar for both studies, and no serious adverse events were observed. Dirlotapide was clinically well-tolerated in dogs at dosages up to 10 mg/kg/day for 14 days and 2.5 mg/kg/day for 3 months. Dirlotapide produced the expected decrease in food intake and body weight (up to 20-40%) without ill effects. Clinical, pathologic, and histopathologic findings were reversible and consistent with suppression of food intake and rapid weight loss produced by elevated dirlotapide dosages. In both studies, sporadic emesis and loose stools were observed in both placebo and dirlotapide-treated dogs. Incidence of emesis generally increased with dose and decreased with treatment time. Elevations in hepatic transaminase activity were seen in dogs treated with more than 1.5 mg/kg dirlotapide daily, but were not associated with clinical signs or microscopic evidence of hepatic degeneration or necrosis.

Efficacy and safety of dirlotapide in the management of obese dogs evaluated in two placebo‐controlled, masked clinical studies in North America

Dirlotapide was evaluated in the management of obesity in dogs in two multicenter, clinical studies in North America. A total of 335 obese dogs of various breeds were randomized to dirlotapide or placebo in a 2:1 ratio. Dirlotapide was administered orally once daily to dogs at an initial dose of 0.05 mg/kg, increased after 14 days to 0.1 (study B, label dose) or 0.2 mg/kg (study A) and then adjusted according to individual weight loss at 28-day intervals. Dogs were examined and weighed, and body condition scores (BCSs) were recorded every 28 days. Study A had three consecutive phases: weight loss (16 weeks, day 0-112); weight management (12 weeks); and post-treatment (8 weeks). Study B had a weight loss phase only. For dirlotapide-treated dogs, mean weight loss by day 112 was 11.8-14.0% compared with 3.0-3.9% for placebo (P = 0.0001). In study A, weight losses for dirlotapide were 19.3% after 12 weeks of weight management and 16.7% (regain of 3.4%) by 8 weeks after dirlotapide was discontinued. In both studies, dogs in both treatments had emesis, lethargy, anorexia, diarrhea, and mildly elevated hepatic transaminase activity, that resolved spontaneously with time. These were experienced more frequently with dirlotapide. Improved activity levels and BCS for >50% dogs were reported with dirlotapide. Dirlotapide was safe and effective in the reduction and management of body weight in obese dogs.

Hepatotoxicity in acute iron poisoning

Although liver injury is a recognized consequence of acute iron poisoning, its description is limited to several case reports. It appears to be dose-related, however, there are published reports of severe iron poisoning without liver injury. The purpose of this study is to examine the hypothesis that this is a dose-related phenomenon and to identify the serum iron concentration of risk for this outcome. The design of this study is a retrospective review of our hospital's experience over 20 years. Extracted data included demographics, time of ingestion, highest serum iron concentration and highest hepatic transaminase activity. Iron poisoning was defined as a serum iron concentration >300 microg/dL (55 micromol/L) within 12 hours of ingestion. Hepatotoxicity was defined as a serum transaminase (either ALT or AST) >150 U/L. Severe hepatotoxicity was defined >1000U/L. Seventy-three patients (1-48 years old) participated in the study and of these patients 60 (47 female) did not have hepatotoxicity. Their serum iron concentrations were 300-704 microg/dL (55-128 micromol/L). Thirteen patients had hepatotoxicity and of these patients, nine had severe liver injury. Severe injury was associated with serum iron concentrations well in excess of 1000 microg/dL (182 micromol/L). Our data support hepatotoxicity due to iron poisoning as a dose-related phenomenon with clinically important cases unlikely with a serum iron concentration of < 700 microg/dL (128 micromol/L) within the first 12 hours. Clinically important hepatotoxicity occurs with values in excess of 1000 microg/dL (182 micromol/L).

Histological Changes in the Liver of Morbidly Obese Patients: Correlation with Metabolic Parameters

Obesity is a major risk factor for fatty liver disease. The purpose of this study was: 1) to determine the degree of steatosis, inflammation and fibrosis in liver biopsies of morbidly obese patients in relation to their body fat distribution and metabolic status, and 2) to examine the course of liver enzyme changes with surgically-induced weight loss. The study population included 179 morbidly obese bariatric surgical patients (82% female, 18% male, mean age 39+/-0.7 (SEM) years, BMI 52+/-0.6 kg/m2, excess body weight 80+/-1.8 kg). All patients tested negative for hepatitis and HIV. Liver biopsies were taken intra-operatively. Hepatic enzyme activities were measured along with lipid parameters, fasting glucose, insulin and leptin. Liver biopsies showed that 47% of morbidly obese females and 85% of males had >30% of hepatocytes filled with fat droplets. Clinically significant hepatic steatosis was associated (P<0.01) with: a) metabolic aberrations, i.e.hyperlipidemia, hyperglycemia, b) male gender, c) abdominal adiposity, and d) elevated hepatic aminotransferase activities. Hepatic inflammation was found in 47% of females and 55% of males, and 'moderate' fibrosis occurred in 12% of males and 6% of females. Postoperatively, the activity of hepatic aminotransferases declined after an initial increase in response to weight loss, with normalization of values occurring at an excess weight loss of 50% (P<0.0001). The majority of morbidly obese patients have >30% steatosis of the liver. The incidence of steatosis is higher for males than females, possibly due to their visceral obesity and associated metabolic aberrations.

Natural history of hepatitis B in perinatally infected carriers

Objectives: To establish natural seroconversion rates and incidence of hepatic pathology in perinatally infected hepatitis B carriers. Methods: Seventy three perinatally infected hepatitis B carriers identified through maternal screening were...

Therapeutic potential of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid in gallium arsenide intoxicated rats.

The dose dependent effects of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid (DMSA) (0.1, 0.3 and 0.5 mmol kg(-1), intraperitoneally (i.p.) once daily for 5 days) to offset the characteristic biochemical, immunological, oxidative stress consequences and DNA damage (based on DNA fragmentation and comet assay) following sub-chronic administration of gallium arsenide and the mobilization of gallium and arsenic were examined. The effects of these chelators alone in normal animals too were examined on above-mentioned variables. Male Wistar rats were exposed to 10 mg kg(-1), GaAs, orally once daily for 12 weeks and were administered DMSA or two of its monoesters (monoisoamyl or monomethyl) for 5 consecutive days. DMSA was used as a positive control. DMSA and its derivatives, when given alone, generally have no adverse effects on various parameters. After 5 days of chelation therapy in GaAs pre-exposed rats, MiADMSA was most effective in the reduction of inhibited blood delta-aminolevulinic acid dehydratase (ALAD) activity and zinc protoporphyrin level while, all three chelators effectively reduced urinary ALA excretion, compared to GaAs alone exposed rats. MiADMSA was also effective, particularly at a dose of 0.3 mmol kg(-1), in enhancing the inhibited hepatic transaminase activities. Parameters indicative of oxidative stress responded less favorably to the chelation therapy, however, three chelators significantly restored the altered immunological variables. MiADMSA was relatively more effective than the other two chelators. GaAs produced significant DNA damage in the liver and kidneys and the chelation treatment had moderate but significant influence in reducing DNA damage. All three chelators significantly reduced arsenic concentration and, however, MiADMSA was more effective than the other two chelators in depleting arsenic concentration from blood and other soft tissues. A dose of 0.3 mmol kg(-1) was found to be relatively better than the other two doses examined. Gallium contents of blood and soft tissues remained uninfluenced by the chelation therapy. Significant loss of copper after MiADMSA administration, however, is of concern and requires further exploration. Additionally, further studies are required for the choice of appropriate dose, duration of treatment and possible toxic/side effects. Keeping in view the promising role of MiADMSA in the treatment of GaAs poisoning, these data will be needed for the registration of this chelating agent as licensed drug for the treatment of gallium arsenide intoxication.

Hepatic tyrosine aminotransferase activity is affected by chronic heat stress and dietary tyrosine in broiler chickens

1. Two experiments were conducted to investigate the impact of high temperature and dietary tyrosine (Tyr) content on performance and activity of hepatic tyrosine aminotransferase (EC 2.6.1.5.), an enzyme that catalyses the first step in the metabolic degradation of Tyr in broiler chickens. 2. Two-week-old birds were allocated to one of three temperature treatments: 24 ° C (control), 36 ° C (heat stress, HS) and 24 ° C pair-fed (24PF) for 2 weeks and fed on diets containing 100% (Experiment 1) and 50, 100 and 200% (Experiment 2) of the NRC requirement for Tyr. 3. In Experiment 1, exposure of chickens to 36 ° C for 2 weeks caused significant increase in hepatic tyrosine aminotransferase activity but no significant change in activity of hepatic phenylalanine 4-hydroxylase (EC 1.14.16.1) (an enzyme that catalyses conversion of phenylalanine to Tyr) compared with the 24PF birds. No significant changes attributable to heat stress were detected in hepatic glutamic-oxaloacetic transaminase (EC 2.6.1.1) activity. 4. In Experiment 2, heat stress caused reductions in weight gain and feed intake in chickens on all diets, compared with their control counterparts. Hepatic tyrosine aminotransferase activity was increased by heat stress compared with their 24PF counterparts in chickens fed on the 100 and 200% Tyr diets, while in chickens fed the 50% Tyr diet, it was reduced by heat stress. 5. From these results, it is suggested that hepatic tyrosine aminotransferase activity is affected by heat stress and dietary Tyr content and the increased tyrosine aminotransferase activity with, in part, relatively low phenylalanine hydroxylase activity in hepatic tissues may be involved in the Tyr metabolism characteristic of heat-stressed chickens.

Human granulocytic ehrlichiosis.

Human granulocytic ehrlichiosis is a recently recognized tick-borne infectious disease, and to date >600 patients have been identified in the United States and Europe. Most patients have presented with a non-specific febrile illness occurring within 4 weeks after tick exposure or tick bite. The risk for serious illness or death increases with advancing age and delayed onset of therapy. Routine laboratory testing may reveal reduced white blood cell and platelet concentrations and mildly elevated hepatic transaminase activity in peripheral blood. A high index of suspicion is necessary to arrive at a timely clinical diagnosis. Patients suspected of having human granulocytic ehrlichiosis (HGE) should be treated with a tetracycline-class antibiotic while awaiting the outcome of confirmatory laboratory testing.

Evaluation of toxicosis of liposome-encapsulated cis-bis-neodecanoato-trans-R, R-1, 2-diaminocyclohexane platinum (II) in clinically normal cats

Abstract Objective To determine adverse effects of single and multiple doses of liposome-encapsulated cis-bis-neodecanoato-trans-R, R-1, 2-diaminocyclohexane platinum (II) (L-NDDP) administered IV to healthy adult cats. Animals 10 healthy adult cats. Procedure 8 cats were given a single dose of L-NDDP (at rates of 75, 100, 150, or 200 mg/m2), and 2 cats were given liposomal lipid (1,500 mg/m2). Six of the 10 cats were given doses of L-NDDP at the maximum tolerated dosage (100 mg/m2) or a lower dosage (75 mg of L-NDDP/m2) at 21-day intervals, for a total of 4 treatments. Hematologic and serum biochemical analyses, urinalyses, and physical examinations were used to monitor effects of L-NDDP. Results All cats had transient pyrexia, lethargy, vomiting (1 to 3 times/24 h), inappetence, and an acute species-specific infusion reaction that was prevented by administration of atropine-diphenhydramine. Dose-limiting toxicosis was evident as a 10- day course of lethargy, intermittent vomiting, and diarrhea. In cats given multiple doses, dose-related thrombocytopenia, cumulative myelosuppression, transient increased hepatic transaminase activity, and mild to moderate hepatic hydropic degeneration and proximal renal tubular lipidosis in excess of lipidosis expected for this species were detected. Bone marrow hypoplasia was detected in some cats that received higher doses (cumulative dosages of 300 or 400 mg of L-NDDP/m2). Conclusion Cats can safely be given L-NDDP at potentially therapeutic dosages without inducing renal or pulmonary toxicoses. Clinical Relevance Because L-NDDP has better tumoricidal activity than cisplatin (in vivo and in vitro) and is not cross resistant, it may be similarly or more efficacious than cisplatin in humans and dogs. (Am J Vet Res 1999;60:257–263)

Is human granulocytic ehrlichiosis a new Lyme disease? Review and comparison of clinical, laboratory, epidemiological, and some biological features.

Human granulocytic ehrlichiosis (HGE) and Lyme disease are caused by infectious agents transmitted by deer ticks (Ixodes scapularis). Because of the shared tick vector and increased seroprevalence of HGE in patients with Lyme disease, there is some confusion about the identity of these infectious agents and the clinicopathologic spectrum of the disease. HGE is an acute febrile illness associated with leukopenia, thrombocytopenia, and increased serum activities of hepatic transaminases. In contrast, Lyme disease is most often subacute, with the frequent presence of erythema migrans rash and infrequent leukopenia, thrombocytopenia, or elevated serum hepatic transaminase activities. Some ehrlichia infections in animals and humans may become persistent, and Ehrlichia-mediated defects in host defense and immune suppression can allow secondary and opportunistic infections. Because of these properties of Ehrlichia species, their role in modifying the clinical course of Lyme disease may be hypothesized and should be tested.

Hepatic ultrasonic changes in workers exposed to perchloroethylene.

To determine if subclinical hepatotoxicity is associated with exposure to perchloroethylene at concentrations commonly experienced in the workplace, and whether surveillance with serum hepatic transaminase activity underestimates such effects. Hepatic parenchymal echogenicity on ultrasonography and serum hepatic transaminase activity were compared in 29 community based dry cleaning operators exposed to perchloroethylene, and a control group of 29 non-exposed laundry workers. Perchloroethylene exposure was assessed by work history and air monitoring. Mean hepatic transaminase activities were minimally increased in dry cleaners compared with laundry workers. Increased alanine aminotransferase activities, between 1.0 and 1.5 times the normal limits, were found in five of 27 (19%) dry cleaners compared with one of 26 (4%) laundry workers. In contrast, diffuse parenchymal changes in echogenicity, as determined by hepatic ultrasonography, were increased nearly twofold in dry cleaners, occurring in 18 of 27 (67%) dry cleaners compared with 10 of 26 (39%) laundry workers (P < 0.05), and were most strongly associated with increased perchloroethylene exposure in older dry to dry or wet transfer operations (odds ratio 4.2, 95% confidence interval 1.1-15.3). Mean eight hour time weighted average perchloroethylene exposure for dry cleaners was 16 ppm, which is less than the permissible exposure limit of 100 ppm in the United States. It was concluded that mild to moderate hepatic parenchymal changes occur more frequently in workers exposed to perchloroethylene than in populations not exposed to chemical solvents, and that these effects are underestimated by serum hepatic transaminase activity.

Hepatic cavitation. A marker of transient hepatocellular injury during biliary lithotripsy.

Sonographically visible microbubbles attributable to cavitation effects have been observed in bile (within the gallbladder), in hepatic vessels, and within the liver of patients undergoing biliary lithotripsy. Cavitation effects are believed to contribute to stone fragmentation and possibly tissue injury during lithotripsy. To study the latter, the relationship between intraparenchymal hepatic cavitation and serum transaminase activity and clinical follow-up was analyzed in 81 patients undergoing 164 lithotripsy treatments. Seventy-one treatments (43%) resulted in sonographically evident microbubbles in the liver parenchyma during lithotripsy. A temporary, yet statistically significant (P < 0.01) rise in SGOT and SGPT was observed within 2 hr of completion of lithotripsy compared to those patients without hepatic microbubbles. All but one patient had a return to pretreatment baseline levels of SGOT and SGPT by two weeks after lithotripsy. In this patient, persistent elevation of transaminases was attributed to the delayed passage of fragments and not to any sequelae from hepatic cavitation effects. Ultrasound immediately after, two weeks after, and 3-12 months after lithotripsy showed no hepatic structural abnormalities. Ursodiol administration at the time of treatment did not predispose to hepatic cavitation or elevation of transaminase. Detection of hepatic microbubbles during lithotripsy is a marker of hepatocellular injury. Their correlation with transaminase elevation refutes the contention that transaminasemia results solely from fragment passage after lithotripsy. Although not associated with recognizable structural damage or long-term sequelae, cavitation effects and transaminasemia reiterate that shockwaves are not entirely benign as they traverse parenchymal organs.

Evidence for the generation of transaminase inhibitor(s) during ethanol metabolism by rat liver homogenates: a potential mechanism for alcohol toxicity.

Since ethanol consumption decreases hepatic aminotransferase activities in vivo, mechanisms of ethanol-mediated transaminase inhibition were explored in vitro using mitochondria-depleted rat liver homogenates. When homogenates were incubated at 37 degrees with 50 mM ethanol for 1 hr, alanine aminotransferase decreased by 20%, while aspartate aminotransferase was unchanged. After 2 hr, aspartate aminotransferase decreased by 20% and by 3 hr, alanine and aspartate aminotransferases were decreased by 31 and 23%, respectively. Levels of acetaldehyde generated during ethanol oxidation were 525 +/- 47 microM at 1 hr, 855 +/- 14 microM at 2 hr, and 1293 +/- 140 microM at 3 hr. Although inhibition of alcohol oxidation with methylpyrazole or cyanide markedly decreased ethanol-mediated transaminase inhibition, neither incubation with acetate nor generation of reducing equivalents by oxidation of lactate, malate, xylitol, or sorbitol altered the activity of either enzyme. However, semicarbazide, an aldehyde scavenger, prevented inhibition of both aminotransferases by ethanol. Moreover, incubation with 5 mM acetaldehyde for 1 hr inhibited alanine and aspartate aminotransferases by 36 and 26%, respectively. Cyanamide, an aldehyde dehydrogenase inhibitor, had little effect on ethanol-mediated transaminase inhibition. Thus, metabolism of ethanol by rat liver homogenates produces transaminase inhibition similar to that described in vivo and this effect requires acetaldehyde generation but not acetaldehyde oxidation. Since addition of pyridoxal 5'-phosphate to assay mixes did not reverse ethanol effects, aminotransferase inhibition does not result from displacement of vitamin B6 coenzymes.

Estradiol-induced hepatic protein synthesis and transaminase activity in the male flounder, Platichthys flesus (L.)

A continued accumulation of vitellogenin was observed in the serum through 28 days after administration of spaced large doses of estradiol. The level of estradiol in the serum reached a maximum on Day 4, followed by a continued decrease until a basal concentration was reached at Day 15. The estradiol treatment increased the in vitro hepatic protein synthesis activity, measured as polyphenylalanine synthesis per unit cytoplasmic RNA, within 2–4 days reaching a maximum after 7 days. The effect was transitory and reduced to less than 50% within 15 days. After restimulation a second rise in protein synthesis activity was observed. The cellular content of bulk RNA in the liver showed a slow but steady accumulation through the 28 days. The specific activity of glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase in the liver decreased 35 and 20% relative to control, respectively, within 7 days after the first stimulation and again 14 days after restimulation. The concentration of serum protein showed a steady increase throughout the experimental period. The concentration of serum ninhydrine positive substances was lowered to 50% relative to the controls within the first 7 days after start of treatment with hormone.

Hepatic lipid deposition and plasma transaminase activity influenced by oral administration of carbon tetrachloride in growing chicks.

Lipid and triglyceride contents in liver and plasma, and plasma transaminase activities were determined in growing White Leghorn male chicks orally administered with carbon tetrachloride (CCl4). Fourteen day administration of CCl4 at rates of 2.5, 5 and 10ml/kg body weight and the single administration at rate of 15 to 30ml/kg body weight increased, with increasing CCl4 doses, liver weight, total lipid and triglyceride contents in the liver, plasma triglyceride concentration and plasma GOT activity but reduced body weight gain and plasma total lipid concentration. Seven out of eight chicks died by 14 day administration of 10 ml CCl4. The maximum increase of the hepatic lipid deposition was demonstrated at 2 or 3 days after whereas that of plasma GOT activity was observed at 1 day after the single administration. It is suggested that a large dose of CCl4 in chicks induces degeneration of hepatic cells, subsequently leading to the hepatic lipid deposition.

Tyrosine transaminase activity in normal and cirrhotic liver.

Most cirrhotics have tyrosinemia and subnormal tyrosine tolerance; in some the ability to metabolize p-hydroxyphenylpyruvic and homogentisic acids is impaired. In previous studies, the initial transamination appeared to be the rate-limiting step. In this study, hepatic tyrosine transaminase activity was compared in liver biopsies from eight noncirrhotic and ten cirrhotic subjects to determine whether the subnormal tyrosine tolerance was related to decreased maximal activity of this enzyme. Fasting plasma tyrosine in the cirrhotics (133 +/- 43 micromol/liter) was significantly higher (P less than 0.005) than in the noncirrhotic subjects (64 +/- 25 micromol/liter). Tyrosine transaminase activity in the cirrhotic livers (42 +/- 11 micromol PHPA/g liver/hr, or 0.47 +/- 0.1 micromol PHPA/mg protein/hr) was not significantly different from the enzyme activity in the noncirrhotic liver (43 +/- 7 micromol PHPA/g liver/hr, or 0.39 +/- .12 micromol PHPA/mg protein/hr.) Thus elevated tyrosine levels in cirrhotics cannot be explained by decreased tyrosine transaminase activity in the liver, and other explanations must be sought.

The influence of sex differences, skin-shedding cycle and hibernation on the regulation of aspartate and alanine aminotransferase activities in the grass-snake, Natrix n. natrix (L.)

1. 1. In the grass-snake, Natrix n. natrix (L.), sex difference are known to have a considerable effect on the regulation of the activities of ASAT, and especially of ALAT. 2. 2. During the inter-moult period the ALAT activities are found to be significantly higher in the liver and serum of the males, the serum activities being higher also during skin-shedding. 3. 3. The very high activity of the enzyme in the serum of the males probably depends on the regulatory effect of a specific protein—the “reptile protein binding testosterone” (RPBT) which binds this hormone on the competitive basis. 4. 4. The activity of ASAT is also relatively higher in the liver and serum of the males. In the course of the shedding cycle no changes in the regulation of the enzymic activities could be seen. 5. 5. The ratios of average hepatic amino transferase activities are clearly different in each sex. However, the ratios of average serum AT activities represent a different range of values. 6. 6. In males, they all confirm the predominance of ALAT activities in the enzymic regulation of the homeostasis of the liver, and of the serum in particular. 7. 7. During moult, the observable changes in the activities of ASAT and ALAT in the liver and serum do not indicate a lowered thyroxin level in the serum of the snakes under study, as postulated by the hormonal model of this process. 8. 8. During hibernation, changes in the regulation of the activities are related primarily to three processes. First, a lowered ASAT activity in the liver differs from that of ALAT. Second, the dispersion of the activities of both enzymes decreases considerably. Third, the numeric values of the ratios of average activities grow for the liver, but they decrease for the serum.

Ascorbic acid and glycosaminoglycan and lipid metabolism in guinea pigs fed normal and atherogenic diets

The effect of low and high doses of ascorbic acid on glycosaminoglycan and lipid metabolism was studied in guinea pigs fed both normal and atherogenic diets. The high dose of ascorbic acid (25 mg/ 100 g body weight/day) decreased the cholesterol level in the liver and aorta but not in the serum in animals fed the normal diet in comparison with those fed the low dose of ascorbic acid (0.1 mg/100 g body weight/day). In animals fed the atherogenic diet, cholesterol decreased in the serum and liver, but not in the aorta. Serum triglycerides were not affected by the dose of ascorbic acid in the group on the normal diet, but in the animals receiving the atherogenic diet, the high dose of ascorbic acid caused serum triglycerides to decrease when compared with the low dose. Hepatic and aortic triglycerides decreased in groups on normal and atherogenic diets receiving the high dose of ascorbic acid. Lipoprotein lipase activity was not affected in the aorta by the dose of ascorbic acid either in the normal or atherogenic diet group. It was increased in the liver and heart in both the groups receiving the low dose of ascorbic acid but decreased in the high dose group. The concentration of all the glycosaminoglycans significantly increased in the aorta of animals on normal diet receiving the high dose of ascorbic acid when compared with the low dose group. In the group on the atherogenic diet, hyaluronic acid was not affected, but all the sulphated glycosaminoglycans increased in the animals receiving the high dose when compared with those receiving the low dose. In the liver all the sulphated glycosaminoglycans increased while hyaluronic acid decreased in both the normal and atherogenic diet groups receiving the high rather than the low dose of ascorbic acid. l-Glutamine: d-fructose-6-phosphate aminotransferase and UDPG dehydrogenase, two key enzymes in the biosynthesis of precursors of glycosaminoglycans, were studied in relation to the dose of ascorbic acid. Hepatic aminotransferase activity was higher both in the normal and atherogenic diet groups when receiving the high rather than the low dose of ascorbic acid. UDPG dehydrogenase was not affected by the dose of ascorbic acid. The activities of the degrading enzymes — hyaluronidase, β-glucuronidase, β-hexosaminidase and aryl sulphatase — significantly increased both in the normal and atherogenic diet groups when receiving the low rather than the high dose of ascorbic acid. The concentration of PAPS, sulphate activity and sulphotransferase activity were all increased in both the normal and atherogenic diet groups receiving the high dose of ascorbic acid.

Effect of some 6-substituted benzo[a]pyrene derivatives upon liver enzymes and ascorbic acid excretion in mice

The effects of benzo[a]pyrene, 6-hydroxymethylbenzo[a]pyrene, benzo[a]-pyrene-6-carboxaldehyde, 6-methylbenzo[a]pyrene, benzo[a]pyrene-6-carbonitrile and benzo[a]pyrene-6-carbonamide on urinary ascorbic acid excretion and hepatic tyrosine transaminase, aniline hydroxylase, aminopyrine N-demethylase and hexobarbital metabolizing activity in mice were examined. The effect of 6-bromobenzo[a]pyrene on the hepatic enzymes was examined. None of the compounds altered aminopyrine N-demethylase or hexobarbital metabolizing activity whilst all produced a statistically significant rise in aniline hydroxylase activity. The tyrosine transaminase activity was increased by 6-hydroxymethylbenzo[a]pyrene but was unaffected by the other compounds. All the compounds raised urinary ascorbic acid excretion after an initial 3 day lag. The level of excretion remained elevated for about a week or more except for 6-hydroxy-methylbenzo [a]pyrene-treated animals which showed a high raised level of excretion for 1 day followed by a drop to a lower than normal level of excretion. The significance of these observations and their relation to other work was discussed.