Biochemical effects of vinyl chloride monomer on the liver of occupationally exposed workers.

We investigated the effects of vinyl chloride monomer exposure on the liver of 86 workers by measuring beta-glucuronidase, arylsulfatase A, adenosine deaminase, 5'-nucleotidase and routine liver function enzymes in the sera of the workers. In 21 of them, three or more of these parameters were raised, with a significant decrease in the level of blood glutathione and a significant increase in the enzyme activity level of glutathione S-transferase. Of these 21 workers, 14 had fatty liver infiltration, 8 of whom were also suffering from liver enlargement. Also, 4 workers had liver enlargement without fatty infiltration and 3 had enlarged spleens. The study highlights the need for vigilance in environmental monitoring and medical surveillance of workers exposed to this chemical.

Biomonitoring of n-nitroso compounds, nitrite and nitrate in the urine of Egyptian bladder cancer patients with or without Schistosoma haematobium infection.

The excretion of nitrate, nitrite, apparent total N-nitroso compounds and volatile nitrosamines was measured in 24 hr urine from 61 Egyptians, divided into 4 groups: controls, Schistosoma haematobium-infected patients and bladder cancer patients with and without a history of schistosomal infection. Urinary nitrate in S. haematobium-infected patients was significantly higher than in the other 3 groups. Nitrite was below the detection limit of the method (

The effect of dimethylnitrosamine on the activities of renal prenolsulfotransferase and arylsulfatases A and B in Schistosona mansoni infected mice.

The activities of renal phenolsulfotransferase and arylsulfatases A and B were estimated in 400 male Swiss albino mice classified into four groups: Normal controls, Schistosoma mansoni infected group, Dimethylnitrosamine (DMN) treated group and infected treated group. The activity levels of the studied enzymes were significantly increased in all groups when compared with the control group, also the statistical analyses showed a high significant increase of the three enzymes levels in the infected treated group; when compared separately with treated or infected groups. It was concluded, therefore, that schistosomal infection is implicated in the development of kidney cancer which may arise from the pattern of hepatic mixed-function oxidase induction characterized for schistosomiasis and its temporal relationship with the procarcinogenic initiating events. Furthermore, the striking significant increase in the enzymatic activity levels of the acid hydrolases arylsulfatases due to the lesion of both cytotoxic effects of dimethylnitrosamine as well as pathological change of schistosomiasis which may play an active role in the initiation of the malignant process by detoxifying endogenous sulfated aromatic metabolites.

Glutathione S-transferase activity and glutathione content in human bladder carcinoma associated with schistosomiasis: comparison with uninvolved surrounding tissues.

Glutathione (GSH), glutathione S-transferase (GST) activity and GSTpi expression were measured in 10 human bladder tumors and adjacent uninvolved specimens from Egyptian patients with a history of schistosomal infection. GSH was higher in the tumor than in surrounding uninvolved tissue (not significant). Total GST activity per mg tissue protein and GSTpi expression were higher in tumor tissues (P < 0.05) than in uninvolved tissues. There was a positive correlation between GST activity and GSH content and between total GST activity and GSTpi expression in both tumor and uninvolved tissues.

In vitro effect of dimethoate on the activity of tryptophan pyrrolase in rat liver.

Total and holo-enzyme activities of tryptophan 2,3-dioxygenase were measured in vitro in the presence and absence of the organophosphorous insecticide, dimethoate. Addition of dimethoate to the reaction mixture decreased the activities of both total and holo-forms. Total and holo-enzyme activities were decreased by 34% and 26%, respectively, by 1 mM dimethoate. On the other hand, 5 mM dimethoate resulted in 56% and 34% inhibition to total and holo-enzyme activities, respectively. Lineweaver-Burk plot of the total-enzyme activity at different tryptophan concentration in the presence of 2 mM dimethoate gave uncompetitive type of inhibition.

Effects of some insecticides on several enzymes of tryptophan metabolism in rats.

The activities of tryptophan 2,3-dioxygenase (EC 1.13.11.11), indoleamine 2,3-dioxygenase (EC 1.13.11.17), kynurenine 3-hydroxylase (EC 1.14.13.9), kynureninase (EC 3.7.1.3), kynurenine transaminases, and pyridoxal phosphokinase (EC 2.7.1.35) in the liver, kidney and lung rats were measured after administration of a single dose and repeated doses of dimethoate, carbaryl and fenvalerate, respectively. Ten percent LD50 of each insecticide was orally administered to a rat for a single dose, while 5% LD50 was orally given for five consecutive days as repeated doses. The control animals received the same volume of vehicle (polyethylene glycol 300). Body weight and organs weight losses were recognized only after repeated doses of dimethoate, while protein content remained constant compared to control animals. Repeated administration of dimethoate caused significant decrease in the activity of kynurenine 3-hydroxylase (28.3% decrease in liver, and 32.5% in kidney), kynurenine-pyruvate transaminase (EC 2.6.1.7) (40% in liver, and 24.2% in kidney), kynurenine- pyruvate transaminase (EC 2.6.1-) (24.5% in kidney) and pyridoxal phosphokinase (36.1% in liver). Repeated doses of carbaryl resulted in a significant decrease in the activity of apo-tryptophan 2,3-dioxygenase (42.8%), kynurenine-2-oxoglutarate transaminase (40% in liver), kynurenine-pyruvate transaminase (30.6% in liver), and serine-glyoxylate transaminase (EC 2.6.1.51) (47.9% in liver). Externally added insecticides at different concentrations to the incubation mixture resulted in an inhibition to tryptophan 2,3-dioxygenase, while the other enzymes examined showed no change in their activities.

In vivo studies on the effect of some insecticides on the hepatic activities of L-tryptophan 2,3-dioxygenase and pyridoxal phosphokinase of male mice.

The effect of Dimethoate, Carbaryl and Permethrin on the activities of liver L-tryptophan 2,3-dioxygenase (total-, holo-, and apo-forms) and pyridoxal phosphokinase of male mice was investigated. Dimethoate inhibited both enzyme systems after single and repeated dose treatment; except the dioxygenase holo-enzyme after repeated doses. Single dose of Carbaryl treatment inhibited the pyridoxal phosphokinase, total and holo-enzyme of L-tryptophan dioxygenase. However, the repeated dose treatment do not affect both enzyme systems. Permethrin inhibited only total-, holo- and apo-enzymes of L-tryptophan dioxygenase whereas repeated administration has no significant effect on both enzymes. The data indicate that these insecticides may induce abnormal tryptophan metabolism through which some endogenous bladder carcinogens are formed.

Biochemical studies on bilharzial and nonbilharzial hyperoxaluria: effect of pyridoxine and allopurinol treatment.

The urinary excretion levels of oxalic acid, calcium, kynurenic, and xanthurenic acids and serum pyridoxal and pyridoxal phosphate concentrations were determined for nonbilharzial and bilharzial hyperoxaluric patients with or without urinary stones. The effects of pyridoxine and allopurinol treatment were also studied. The different groups studied showed elevated levels of urinary oxalic acid, calcium, kynurenic, and xanthurenic acids as well as decreases in serum pyridoxal and pyridoxal phosphate concentrations. These data indicate that nonbilharzial hyperoxaluric patients suffer from dietary B6 deficiency, whereas bilharzial hyperoxaluric patients may suffer from impaired pyridoxine phosphokinase activity. Pyridoxine supplementation is recommended for the treatment of nonbilharzial hyperoxaluric patients. Allopurinol may be the proper drug in the treatment of oxaluria and stone formation or of bilharzial patients.

Effect of gossypol on liver metabolic enzymes in male rats.

The effects of gossypol on liver metabolism were examined in male rats. Gossypol acetic acid was administered to Sprague-Dawley rats intraperitoneally (i.p.) at 5 mg/kg daily, 5 days/week for 2 weeks. The rats were killed 24 h after the last injection. The liver/body weight ratio (-42%), concentration of liver glutathione (-34%), activities of liver alpha-naphthtylacetate esterase (-30%) and DNase (-39%) were significantly decreased when compared to controls. Hepatic beta-glucuronidase (+37%), RNase (+35%) and serum alkaline RNase (+23%) activities were significantly increased. No changes were found in serum transaminases (SGPT, SGOT) or in hepatic RNA and DNA concentration. Elevation of liver and serum RNase activities suggest that gossypol treatment produces some catabolic effects. The depletion of hepatic glutathione and the elevation of beta-glucuronidase activity indicate that gossypol is hepatotoxic when given at this dose for 2 weeks.

Hepatic microsomal enzymes in Schistosoma mansoni-infected mice: I. Effect of duration of infection and lindane administration on dimethylnitrosamine demethylases.

The prevalence of schistosomiasis in Egypt, its suspected relationship to carcinoma of the bladder, and the inevitable exposure of schistosomal patients to insecticides prompted the undertaking of this study. Dimethylnitrosamine (DMN) demethylases, responsible for the activation of DMN, were assessed in the hepatic microsomes from albino mice under the influence of Schistosoma mansoni infection and/or lindane administration. DMN-demethylase I responded to infection by an early increase in activity, reaching a peak 30 days after disease induction and declining sharply afterwards. DMN-demethylase II followed the same general pattern, but it reached its peak 20 days after infection and declined at a slower rate than DMN-demethylase I. The effects of lindane, an organochlorine insecticide, were also studied on these two enzymes in uninfected mice and in S. mansoni-infected animals after different durations of disease induction. Given orally, in a dose of 40 mg/kg/day for 3 consecutive days, lindane increased the activity of both enzymes. Since DMN requires metabolic activation for its hepatotoxic and carcinogenic actions, alterations in its activating enzymes, as a consequence to schistosomiasis and/or exposure to lindane, may change susceptibility to its toxic and carcinogenic potentials.

Hepatic microsomal enzymes in S. mansoni infected mice: II. Effect of duration of infection and lindane administration on aminopyrine demethylase and aniline hydroxylase.

The time course of effects of S. mansoni infection on hepatic microsomal drug metabolizing enzymes was studied in swiss albino mice. Aminopyrine demethylase and aniline hydroxylase showed increases in activity, reaching a peak 30 days post infection. Both enzymes demonstrated a steady decline thereafter. On day 60, the level of aminopyrine demethylase was comparable to that of uninfected mice. On the other hand, the activity of aniline hydroxylase was lower than the control values. Treatment with lindane (40 mg/Kg/day X 3) increased the activity of both enzymes after different durations of disease induction. Changes in hepatic microsomal enzymes in S. mansoni infection may alter the intensity and duration of pharmacologic or toxic effects of drugs eliminated from the body through metabolic transformation.

Steroidal thiourea and thiazoline derivatives: synthesis and in vitro effects on bovine pancreatic ribonuclease activity.

Two novel series of steroidal derivatives containing various thiourea and substituted thiazoline moieties attached to the 2- or 4-position of estrone were synthesized and examined for in vitro effect on bovine pancreatic ribonuclease activity. All compounds studied exhibited a catabolic activity. The steroidal thiazoline derivatives were more potent activators of ribonuclease than the steroidal thioureas.

Influence of pretreatment with various insecticides on the N-demethylation of dimethylnitrosamine.

The effects of various classes of insecticides were studied on the N-demethylation of dimethylnitrosamine (DMN) by mouse liver enzymes. Organochlorine insecticides, represented by lindane, DDT, and endrin, increased the activities of DMN demethylase I and II. The latter enzyme was more susceptible to the inducive action of the tested chlorinated insecticides. On the other hand, the synthetic pyrethroids, fenvalerate and flucythrinate, did not alter the activity of either enzyme. While pretreatment with carbaryl, a carbamate derivative, was without effect, moderate elevation in the activity of both demethylases was observed following administration of carbofuran. Dimethoate, representing organophosphorus compounds, was the only insecticide tested to inhibit the N-demethylation of DMN, with more pronounced effect on DMN demethylase I. Since DMN requires metabolic activation for its hepatotoxic and carcinogenic actions, alterations in the activities of its metabolizing enzymes as a sequela of exposure to certain insecticides may change susceptibility to its toxicity and/or carcinogenicity.

Steroidal derivatives. Part 4: Synthesis and in vitro anabolic and catabolic properties of a new group of steroidal alkylating agents.

A new group of steroidal alkylating agents has been synthesized for potential anticancer activity. The compounds contain a sulfonic ester, a mono- or a bifunctional nitrogen mustard function attached to an ethyl chain and forming ether linkages at the 3- or 17 beta-position of the steroids selected. The products were tested for their in vitro anabolic and catabolic properties by measuring their effects on the bovine pancreatic ribonuclease.

Effect of some xenobiotics on kynurenine hydrolase and kynurenine aminotransferase of mouse liver.

The effects of some xenobiotics on the activity of the B6-dependent kynurenine hydrolase (KH) and kynurenine aminotransferase (KATE) in mouse liver, were investigated. Polychlorinated biphenyl (Aroclor 1254) (400mg/kg/day x4) markedly decreased the activity of both enzymes. Benzo(a)pyrene (BP) and 3-methylcholanthrene (3-MC) (40mg/Kg/day x1) as well as phenobarbital (PB) (75mg/kg/day x3) did not alter the activity of KH, while that of KATE was mildy reduced. The response of the two enzymes to treatment with chlorpromazine (CPZ) (5mg/Kg/day x5) were opposite with marked elevation of KH and inhibition of KATE activities. Treatment with B-naphthoflavone (B-NF) (80mg/Kg/day x2), Pyrazole (200mg/Kg/day x1) or indole (400mg/kg/day x1) produce no change in the activity of either enzyme. It, seems therefore, that Aroclor (1254) and chlorpromazine may cause disordered kynurenine metabolism through alterations in the activities of its metabolizing enzymes. This, in turn, might affect nicotinamide adenine dinucleotide biosynthesis and/or the accumulation of some tryptophan metabolites suspected of being carcinogenic or co-carcinogenic.

In vivo and in vitro studies on the effects of some phenothiazines and sulpiride on kynurenine metabolism.

The effect of 5 consecutive daily i.p. doses of CPZ (5 mg/kg), PZ (10 mg/kg) and PMZ (10 mg/kg) on the activity of kynurenine hydrolase and kynurenine aminotransferase in mouse liver was studied. All three phenothiazines effected an increase in the activity of kynurenine hydrolase per unit weight of liver with CPZ showing the highest activation followed by PZ and PMZ. On the other hand kynurenine aminotransferase was more moderately inhibited by the above treatment. In vitro studies showed that the phenothiazines tested and the pharmacologically inactive CPZO, the major metabolite of CPZ, in concentrations ranging from 3 X 10(-9) to 3 X 10(-4) M had an activating effect on kynurenine hydrolase. Increases in activity were obtained up to concentrations of 3 X 10(-6) M and levelled off afterwards. The highest increases were observed with CPZ and CPZO, while those of PZ and PMZ were of lesser magnitude. However, the tested phenothiazines were without effect on kynurenine aminotransferase. The newly introduced psychotropic drug, sulpiride, which is a substituted benzamide, was devoid of activity on either enzyme both in vivo (50 mg/kg) and in vitro (3 X 10(-9) to 3 X 10(-4) M).

Effect and mechanism of action of methomyl and cypermethrin insecticides on kynurenine metabolizing enzymes of mouse liver.

The effect of methomyl and cypermethrin insecticides on the B6-dependent kynurenine hydrolase (KH) and kynurenine aminotransferase (KATE) was studied. These insecticides induced pronounced inhibition on the (KH) and (KATE) enzymes after single dose treatment. Repeated doses of methomyl induced inhibition on the (KH) and (KATE) activities, whereas repeated treatment with cypermethrin had no effect on the activities of these enzymes. In vitro methomyl inhibited (KH) and (KATE) enzymes at 10(-6)M up to 10(-3)M, through a competitive mechanism. Methomyl and cypermethrin are capable of causing alterations in the kynurenine metabolizing enzymes of mouse liver.

Effect of fenvalerate on kynurenine metabolizing enzymes and acid ribonuclease of mouse liver.

The effects of fenvalerate, a pyrethroid insecticide, were studied on some mouse liver enzymes. Given orally, either in a single dose of 60 mg/kg or in a six daily doses of 20 mg/kg, fenvalerate reduced the activity of the B6-dependent kynurenine hydrolase (KH), but increased that of kynurenine aminotransferase (KATE) and beta-glucuronidase (beta-Glase). While the single dose treatment with fenvalerate had no effect on acid ribonuclease (RNase), the repeated treatments increased the activity of this enzyme. This study demonstrates that fenvalerate can alter the kynurenine metabolizing enzymes and acid ribonuclease of mouse liver.