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J Mohandas

Publications and source records attributed to J Mohandas.

9 recordsLinked to original sources
PubMed1986

Sex-dependent activities of quinone reductases in rabbits indicate higher risk of bladder cancer in the male.

The distribution of NADPH-dependent quinone reductase and NADPH-cytochrome P-450 reductase activities was determined in the urinary bladders of male and female rabbits. In urinary bladder transitional epithelium (UBTE) and in urinary bladder non-transitional tissue (UBNT) microsomal quinone reductases demonstrated significant (P less than 0.05) sex-dependent differences in the case of both dicoumarol-insensitive (male greater than female) and dicoumarol-sensitive or DT-diaphorase (female greater than male) activities. Microsomal NADPH-cytochrome P-450 reductase activities in UBTE and in UBNT were found to be similar in male and female rabbits. The activities of microsomal and cytosolic quinone reductases and the activity of microsomal NADPH-cytochrome P-450 reductase in UBNT were much lower than those in UBTE. NADPH-cytochrome P-450 reductase and similar flavo-enzymes activate quinones via one-electron reduction into semiquinone free radicals, which then react with molecular oxygen, forming superoxide anions. DT-diaphorase acts as a detoxifying enzyme by converting many quinones via a unique two-electron reduction into less reactive hydroquinones, enabling their excretion as water-soluble conjugates. Since UBTE contains substantial activities of prostaglandin H synthase (PHS) and NADPH-cytochrome P-450 reductase, unlike UBNT, the toxicity and carcinogenicity of xenobiotics which are either quinones or form quinones in situ through the mediation of PHS would be high in UBTE. The risk of carcinogenicity of quinones in UBTE would be higher in male rabbits than in female rabbits due to sex-dependent differences in the relative proportions of the one-electron reduction pathway, represented by NADPH-cytochrome P-450 reductase, and the two-electron reduction pathway, represented by DT-diaphorase (female greater than male).

Animals↗
PubMed1984

Differential distribution of glutathione and glutathione-related enzymes in rabbit kidney. Possible implications in analgesic nephropathy.

Whole tissue reduced glutathione (GSH) concentration was found to be lowest in rabbit renal inner medulla and progressively higher in outer medulla and cortex. Activities of cytosolic glutathione reductase in inner medulla and outer medulla were similar, and each was only approximately 50% of that of cortex. Whole tissue and microsomal gamma-glutamyl transpeptidase activities were high in cortex and outer medulla but were low in inner medulla. Cytosolic activity of selenium-dependent glutathione peroxidase ( GPx -I) was similar in both outer medulla and inner medulla but was only 50% of that of cortex. Activity of cytosolic selenium-independent glutathione peroxidase ( GPx -II) was highest in cortex and lowest in inner medulla (approximately 15% of cortex and approximately 50% of outer medulla). Cytosolic glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene as substrate was high in all three regions of kidney. With 1,2-dichloro-4-nitrobenzene and 1,2-epoxy-(4-nitrophenoxy)propane as substrates, cytosolic glutathione S-transferase activities were very low in cortex, outer medulla, and inner medulla. Microsomal activities of glutathione reductase, GPx -I, GPx -II and glutathione S-transferases were much lower than activities of corresponding cytosolic enzymes. Activities of the glutathione peroxidases in renal inner medulla would hence be expected to cause little interference to prostaglandin endoperoxide synthetase mediated cooxidative activation of paracetamol. It has been demonstrated that the paracetamol metabolite can react rapidly with GSH, forming not only glutathione conjugate but also paracetamol itself and oxidized glutathione. Low GSH concentrations, as well as low activities of glutathione reductase, GPx -I, GPx -II, and gamma-glutamyl transpeptidase, may therefore render the inner medullary region of kidney particularly vulnerable to paracetamol-related analgesic nephropathy.

Acetaminophen↗
PubMed1984

Low activities of glutathione-related enzymes as factors in the genesis of urinary bladder cancer.

A comparative study of reduced glutathione (GSH) concentrations and activities of GSH related-enzymes in urinary bladder transitional epithelium (UBTE), urinary bladder nontransitional tissue (UBNT), and liver of the rabbit, was carried out to investigate the reasons for the susceptibility of UBTE towards peroxidase-mediated chemical carcinogenesis. Cooxidative activation of chemical carcinogens by prostaglandin H synthase occurs at high levels in UBTE and minimally in UBNT. Other peroxidases are also likely to activate carcinogenic xenobiotics in the urinary bladder. GSH concentrations in UBTE and UBNT were low compared to that in the liver. gamma-Glutamyl transpeptidase activities were much lower in UBTE and in UBNT than those in the liver. Activities of selenium-dependent and selenium-independent glutathione peroxidases were very low in UBTE and UBNT. Cytosolic glutathione S-transferase activity towards 1,2-epoxy-(4-nitrophenoxy)propane was very low in UBTE. Microsomal glutathione S-transferase activity towards 1-chloro-2,4-dinitrobenzene was much lower in UBTE than in the liver. We propose that the low GSH concentration and diminished activities of glutathione peroxidases, gamma-glutamyl transpeptidase, and certain isozymes of glutathione S-transferase could be responsible for the vulnerability of UBTE towards chemical carcinogenesis.

Animals↗
PubMed1984

DT-diaphorase: differential distribution in rabbit kidney and possible protection against quinone toxicity in the inner medulla.

DT-diaphorase, presently regarded as a protective enzyme against quinone toxicity, was found to increase in activity from cortex to inner medulla within the rabbit kidney. The high activity of DT-diaphorase in renal inner medulla would therefore provide effective protection in that region of kidney against toxicity and carcinogenicity of xenobiotics which are either quinones or converted to quinones via prostaglandin H synthase.

Animals↗
PubMed1981

A disarmed world.

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Acetaminophen↗
PubMed1981

Regional differences in peroxidatic activation of paracetamol (acetaminophen) mediated by cytochrome P450 and prostaglandin endoperoxide synthetase in rabbit kidney.

Microsomes from renal cortex, outer medulla, and inner medulla of rabbit kidneys were found to catalyze the metabolic activation of paracetamol (acetaminophen), leading to covalent binding to protein when incubated with cumene hydroperoxide and T-butyl hydroperoxide. Differential distribution of cytochrome P450 and prostaglandin endoperoxide synthetase and each enzyme's preference for either cumene hydroperoxide or T-butyl hydroperoxide enabled the present investigation to distinguish their respective contributions in the cooxidative activation of paracetamol. Addition of methemoglobin caused enhancement of prostaglandin endoperoxide synthetase mediated activation of paracetamol when initiated by both arachidonic acid and the hydroperoxides. Aspirin and indomethacin inhibited the protein covalent binding of the reactive metabolite of paracetamol only when its formation was initiated by arachidonic acid. This study demonstrates the differences in the peroxidation metabolic activation of paracetamol mediated by cytochrome P450 (cortex greater than outer medulla greater than inner medulla) and prostaglandin endoperoxide synthetase (inner medulla greater than outer medulla greater than cortex) in rabbit kidney.

Acetaminophen↗
PubMed1978

Aspirin, protein transacetylation and inhibition of prostaglandin synthetase in the kidney.

1 The effect of aspirin on the kidney has been investigated in mice and rabbits. [Acetyl-(14)C]-aspirin was administered intraperitoneally in doses ranging from subtherapeutic to toxic. The degree of acetylation of protein was determined by the radioactivity remaining on protein precipitates of renal cortex and medulla after sequential washing designed to remove non-covalently bound material. Controls were established, by the use of [carboxyl-(14)C]-aspirin.2 The acetyl-(14)C residue was bound to renal proteins in a linear manner in increasing amounts with increasing dosage up to 100 mg/kg. The [carboxyl-(14)C]-aspirin was not bound and thus the salicylate portion of the molecule was not bound covalently to the renal protein. The time course of the acetylation was rapid, consistent with the rate of aspirin absorption. The disappearance of acetylated protein was slow, with a T(1/2) of 112.5 h in the renal cortex, and 129.5 h in the renal medulla.3 Differential centrifugation, Sephadex chromatography and gel electrophoresis were carried out on tissue homogenates to determine the site of acetylation. The acetylation was greatest in the microsomal fraction, although all protein fractions showed some degree of acetylation.4 The prostaglandin synthetase activity of a particulate preparation from rabbit kidney was determined by a spectrophotometric assay of malondialdehyde formation. Aspirin (10 mg/kg, i.v.) significantly inhibited prostaglandin synthetase in the renal cortex and medulla.5 Aspirin and renal proteins undergo a transacetylation reaction resulting in stable acetylated protein, with acetylation being greatest in the microsomal fraction. Aspirin has been shown to inhibit prostaglandin synthetase and this could lead to functional impairment of the tissue.

Acetylation↗