Biomedical subjects
Publications and source records attributed to H Mukhtar.
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Rats injected i.p. with acrylamide (50 mg/kg/day) for 5 days showed a significant inhibition of hepatic glutathione-S-transferase (GST) activity; maximum inhibition occurred in 15-day-old rats in which early development of hind limb paralysis was noted. Addition of acrylamide in vitro to the assay system also inhibited GST activity. No changes were observed in oxidized and reduced glutathione contents.
Acrylamide, a reactive electrophile, caused a concentration-dependent inhibition of alcohol dehydrogenase (ADH) activity (purified) which was reversed by prior addition of glutathione. Reaction of thiol groups of this enzyme with orthophthalaldehyde (OPT), a fluorescent reagent, exhibited characteristic fluorescence maxima at 330 nm excitation and 420 nm emission. Addition of acrylamide to the enzyme resulted in a concentration-dependent (acrylamide and protein) quenching of fluorescence of thiol groups when compared with fluorescence quenching caused by N-ethylmaleimide (NEM), a known thiol ligand. The results demonstrate that acrylamide-induced inhibition of purified ADH activity is mediated through its specific interaction with -SH groups in the enzyme molecule.
Glutathione-S-transferase activity in the brain of male mammals (rat and mouse) was found to be relatively lower than in that of females. In contrast, the male aves (pigeon, kite, vulture, and crow) exhibited comparatively higher activity in brain glutathione-S-transferase than the corresponding females. Postnatal development of cytosolic glutathione-S-transferase activity in the rat brain was also investigated. The day-7 rats showed a low activity of 48 nmol/min/mg protein that gradually increased 3.2-fold over the age of 28 days. No striking differences in brain enzyme activities were observed between the 35- and 90-day-old rats. Discrete brain regions of immature rats were found to possess considerable but lower quantities of glutathione-S-transferase activity than those of the adults. The activity increased with the onset of development and attained a steady state after 21 days of age.
Quantitative estimations of glutathione S-transferase activities with 1-chloro-2,4-dinitrobenzene as the electrophilic second substrate, in 142 postmortem human tissue specimens derived from 34 different organs of one or more of 13 individuals belonging to various age groups, are presented. Collectively the data indicate: (1) all tissues examined have appreciable levels of enzyme activity; (2) liver, kidney, lung, muscle, heart, adrenal glands, pancreas, and stomach of fetal origin possess higher enzyme activities than those of the adults, and (3) there are wide interindividual variations in the tissue enzyme activities.
1. Rat liver mitochondrial microsomal glutathione (GSH) S-transferase activities with 1-chloro-2,4-dinitrobenzene as substrate were 11.0 and 11.6%, and with 1,2-dichloro-4-nitrobenzene as substrate were 27.7 and 15.4%, of the corresponding cytosolic activities respectively. 2. Marked difference in inducibility of cytosolic and particulate GSH S-transferase activities were seen after pretreatment of animals with enzyme-inducing agents. 3-Methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin enhanced cytosolic GSH S-transferase activity only. Phenobarbital induced the cytosolic and microsomal enzymes only.
1. Benzo[a]pyrene hydroxylase, aminopyrine demethylase and glutathione S-transferase activities in hepatic and extrahepatic tissues of five wild birds, rat and mouse were compared. 2. Hepatic benzo[a]pyrene hydroxylase of wild pigeon was at least three times higher than that of rat or mouse. Hepatic aminopyrine demethylase and GSH S-transferase activities of wild birds were lower than those of rodents. 3. Renal GSH S-transferase of wild birds was 2-3 times more than in rat and mouse. 4. Avian benzo[a]pyrene hydroxylase activity of hepatic and renal tissue was linear up to 3.0 mg enzyme protein with pH optima of 7.4 and 7.2, at 42 degrees C. Apparent Km values were 11.76 and 3.33 microM respectively. 5. Hepatic enzyme activity was induced four-fold by 3-methylcholanthrene and about two-fold by phenobarbitone administration.
Toxicological studies of a leachable stabilizer Di-n-butyltin dilaurate (DBTL) were undertaken. Effects of DBTL after 15 days oral exposure to rats were studied on brain and liver enzyme activities. A significant decrease in body weight gain of DBTL exposed rats were observed. No effect was observed in the activities of brain enzymes, succinic dehydrogenase, adenosine triphosphatase, acetylcholine esterase and monoamine oxidase. In liver, DBTL treatment resulted in a significant decrease in the activities of microsomal enzymes glucose-6-phosphatase, aminopyrine-N-demethylase, benzphetamine-N-demethylase, aniline hydroxylase, benzo(a)pyrene hydroxylase and also on cytochrome P-450 content, whereas no difference in the activities of mitochondrial enzymes, succinic dehydrogenase, Mg2+-adenosine triphosphatase as well as in the activity of lysosomal enzyme acid phosphatase was observed. Duration of exposure dependent increase in pentabarbital induced sleeping time was also observed. DBTL treatment produced an induction in heme oxygenase activity whereas the activity of -aminolevulinic acid synthetase remained unaltered. The results demonstrate that DBTL significantly affects the biotransformation mechanism and heme metabolism of hepatocytes.
Glutathione-S-transferase activity has been demonstrated in the brain of rabbit, guinea pig, rat, mouse, and pigeon. The activity was in the following order: rabbit > (guinea pig = mouse) > rat > pigeon. The activity of brain was about 1/3 to 1/9 of that present in liver depending upon the species. In the rat brain glutathione-S-transferase activity was found to be distributed equally in cerebrum, cerebellum, and brain stem and localized mainly in the organelle-free cytosol fraction.
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The formation of p-nitrophenylglucuronide from p-nitrophenol and [14C]uridine disphosphoglucuronic acid was demonstrated in intact rat liver nuclei and nuclear membranes. Most of the enzymatic activity in nuclei (80%) was localized in the nuclear envelope. Several in vitro activators of microsomal glucuronyltransferase had no effect on enzyme activity in whole nuclei, but were effective in stimulating the activity in nuclear membranes; however, the magnitude of activation (45%) was much less than with microsomes (500%). UDP-N-acetylglucosamine had no effect on nuclear UDP-glucuronyltransferase activity in whole nuclei or in nuclear membrane preparations. The nuclear membrane enzyme(s) did not obey simple Michaelis-Menten kinetics in native or detergent-activated enzyme preparations. The kinetic behavior did not change upon activation and the apparent Km values remained constant, 1.0 and 0.7 mM for UDP-glucuronic acid and nitrophenol, respectively. Nuclear membrane UDP-glucuronyltransferase activity was increased 3-fold by pretreatment with 3-methylcholanthrene. Phenobarbital or trans-stilbene oxide pretreatment had no effect on nuclear enzyme activity. In contrast, microsomal UDP-glucuronyltransferase activity was increased upon pretreatment with all of these inducers. The results suggest that rat hepatic nuclear glycuronyltransferase activity is localized in the nuclear envelope and that the activity is possibly under a different control mechanism than tha for the microsomes. The properties and physiological significance of the nuclear enzyme are discussed.
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After 2 and 7 days on n-octane and n-nonane administration (intraperitoneally) to female albino rats, alterations in the levels of hepatic xenobiotic metabolising enzyme activities and TBA reactants were observed. Fifty to eighty per cent reduction in the specific activities of benzo[a]pyrene hydroxylase, benzphetamine-N-demethylase, p-nitroanisole-O-demethylase and glutathione-S-transferase were observed. Cytochrome P-450 and free sulfhydryl contents of liver were also decreased significantly after 7 days treatment on n-octane and n-nonane. A 2- and 3- fold increase in liver lipid peroxidation estimated as TBA reactants was observed in the animals treated for 2 or 7 days with n-octane or n-nonane.
Pre-administration of diethyl maleate (DEM) to rats resulted in an earlier onset and development of hind limb paralysis following acrylamide administration than in rats treated with acrylamide only. A marked depletion of brain biogenic amine content and of glutathione levels was also observed in the DEM pretreated groups. Depletion of cellular glutathione would appear to lead to an increased neurotoxicity of acrylamide.
Since the male gonad is a target organ of both pituitary hormones and androgens, the present study was performed to determine whether testicular aryl hydrocarbon hydroxylase (AHH), epoxide hydrase (EH), and glutathione transferase activities and cytochrome P-450 levels were regulated by follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Intact, sham-operated controls and hypophysectomized (HYPOX) male rats were used. Forty days after HYPOX, rats received three daily injections of LH, FSH, testosterone, or LH plus FSH (100 microgram each), or 0.15 M NaCl. Rats were killed 5, 10, and 15 days after hormone administration. In HYPOX rats, testicular AHH and EH activities and P-450 content were significantly reduced at all time points (20 to 70% of sham-operated control values), but glutathione transferase activity was unchanged. In contrast, testicular AHH, EH, and P-450 were significantly induced in all LH treatment groups but not in FSH or testosterone treatment groups. The highest induction with LH was found in the 15-day treatment group (5- to 14-fold that of 0.15 M NaCl-treated HYPOX control). Since Leydig cells are target cells of LH, the result suggests that LH-stimulated induction of testicular AHH and EH activities and P-450 contents may be primarily associated with the interstitial cell compartment.
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