Sialic acid metabolism in regenerating rat liver

Sialic acid metabolism was investigated in control rat liver, in regenerating liver at 24 h and 48 h after partial hepatectomy and in the liver of sham-operated animals. High levels of membrane-bound neuramindase, with no detectable changes in the soluble enzyme, were observed in regenerating rat liver. The neuraminidase activities in the liver of sham-operated rats were identical to those present in control liver. High levels of CMP-N-acetylneuraminic acid synthetase and sialyltransferase were observed both in regenerating liver as well as in the liver of sham-operated rats. The sialic acid content of regenerating rat liver, which was lower than that found in the liver of control and sham-operated rats at 24 h, returned to normal values 48 h after surgery.     

The effect of neonatal administration of sex hormones on ribonucleic acid metabolism in the liver of male and female rats

Fifteen minutes after the intraperitoneal injection of ³²P labelled phosphate, normal adult male rats show a higher incorporation of isotope into their liver nuclear RNA than do females. A single injection of testosterone into neonatal female rats causes a higher uptake of ³²P in adult life, while a single injection of oestradiol into male neonates lowers the incorporation in adult life. Gonadectomy at 4 weeks of age has only a small effect on the subsequent incorporation of ³²P into nuclear RNA either in control rats or in rats injected with sex hormones immediately after birth, showing that this effect of liver metabolism is mainly determined by the hormanal pattern at about the time of birth. The possible relevance of this sex difference in RNA metabolism to the different sex incidence of spontaneous or induced liver cancer is discussed.     

First-pass metabolism of pentamethylmelamine in the rat liver

The disposition of pentamethylmelamine (PMM) was studied in the male Wistar rat. PMM (5 mg/kg) was administered intraarterially, i.v. (5 and 10 mg/kg), via the portal vein, and into the duodenum to cannulated and unanesthetized rats (n greater than or equal to 4) via infusion. Parent compound and metabolites were quantified by gas chromatography. The areas under the plasma concentration-time curves of PMM after intraarterial and i.v. administration were equal and twice as large as the areas after portal vein and intraduodenal administration. This indicated insignificant lung metabolism for PMM; the low bioavailability of PMM when given via the portal vein or intraduodenally (in both cases, some 50% of an i.v. dose) was the result of presystemic metabolism in the liver. PMM was completely absorbed after intraduodenal administration, and no intestinal metabolism was observed. Linear kinetic behavior of i.v. PMM was observed in the 5- to 10-mg/kg dose range. The area under the plasma concentration-time curve of the first metabolite N2,N2,N4,N6-tetramethylmelamine was significantly greater when PMM was given via the portal vein or intraduodenally than when given intraarterially or i.v. This indicated either extrahepatic elimination/renal excretion of PMM or the existence of an additional metabolic pathway. However, experiments with adrenalectomized rats and rats with ligated blood flow to the kidneys did not alter the area for the first metabolite. These findings may be explained by the formation of unknown metabolites and/or reactive intermediates of PMM.     

The metabolism of 9,10-dimethylanthracene by rat liver microsomal preparations

The metabolism of the weakly-carcinogenic hydrocarbon, 9,l0-dimethylanthracene(DMA) by rat-liver microsomal preparations has been examined.9-Hydroxymethyl-10-methylanthracene (9-OHMeMA) and 9,10-dihydroxymethyl-anthracene(9,l0-DIOHMeA) were identified as metabolites .by comparingtheir chromatographic and spectral properties with those ofthe authentic compounds. The trans-1,2-dihydro-1,2-dihydroxyderivative of DMA (DMA 1,2-diol) was the major metabolite formedwhich was identified by its chromatographic, u.v., n.m.r. andmass spectral properties. The dihydrodiol was also formed inthe oxidation of DMA in an ascorbic acid-ferrous sulphate-EDTAsystem. Two other dihydrodiol that were formed from DMA by metabolismappeared to be the trans-1,2-and 3,4-dihydrodiols of 9-OHMeMA(9-OHMeMA 1,2-diol and 9-OHMeMA 3,4-diol) and the further metabolismof DMA 1,2-diol yielded both of these dihydrodiols. When 9-OHMeMAwas further metabolized, two main metabolites were formed; onewas identified as 9,10-DiOHMeA and the other appeared to be9-OHMeMA 3,4-diol. No metabolites were detected when 9,10-DiOHMeAwas incubated with rat-liver microsomal fractions.     

Mitoxantrone metabolism in the isolated perfused rat liver

Summary The hepatobiliary pharmacokinetics of mitoxantrone, a new anthracenedione derivative, was studied in the isolated perfused rat liver. Mitoxantrone was administered in doses of 0.2 and 0.4 mg/kg body weight. Multiple bile samples were obtained for 4 hours. Mitoxantrone and three metabolites were separated by high-performance thin-layer chromatography (HPTLC) and measured at 610 nm.Following 0.2 mg mitroxantrone/kg body wt, 25.8%±2.6% of the administered dose was excreted in the bile during 4 h, the major metabolite M₁ accounting for 80% of this. After 0.4 mg mitoxantrone/kg body wt the amounts excreted were lower and light microscopic examination showed disseminated areas of cell necrosis.     

Tamoxifen stimulates arachidonic acid release from rat liver cells by an estrogen receptor-independent,non-genomic mechanism

Background  

Tamoxifen is widely prescribed for the treatment of breast cancer. Its success has been attributed to the modulation of the estrogen receptor. I have previously proposed that the release of arachidonic acid from cells may also mediate cancer prevention.     

The predominant role of S-oxidation in rat liver metabolism of thiaarenes

Thiaarenes are metabolized by liver microsomes of untreated rats predominantly to sulfones and sulfoxides. After pretreatment of rats with monooxygenase inducers, ring oxidation of thiaarenes is also observed. In case of benzo[b]naphtho[2,3-d]thiophene the formation of a p-quinone takes place. Rat liver microsomal metabolism of the thiaarenes tested as substrates did not resemble that of the polycyclic aromatic hydrocarbon (PAH) isosters at all.     

Positive influence of dietary deoxycholic acid on development of pre-neoplastic lesions initated by N-methyl-Nnitrosourea in rat liver

The effect of deoxycholic acid (DCA) treatment subsequent toinitiation of F344 male rats with N-methyl-N-nitrosourea (MNU),a wide spectrum carcinogen inducing tumors in many organs, wasinvestigated. Rats were initially given four doses of MNU (50mg/kg) i.p. within a 2-week period combined with a two-thirdspartial hepatectomy performed at day 7 and then placed on basaldiet containing DCA at concentrations of 0.313, 0.125, 0.050and 0.020% for 21 weeks prior to final sacrifice. All organsstudied were carefully examined histologkally and histochemicallyfor development of neoplastic and pre-neoplastic lesions. DCAenhanced the induction of glutathione S-transferase positive(GST-P+) liver cell foci in a dose-related manner. Furthermoregroups of rats given DCA without prior MNU administration alsodeveloped dosedependent numbers of pre-neoplastic liver lesions.In addition, increased numbers of small intestine tumors wereapparent in DCA-treated animals although the difference wasnot significant. Induction of tumors in the thyroids, Zymbalglands, skin and peripheral nerves was not affected. The resultsindicate that DCA is a strong promoter of hepatocarcinogenesiswith possible complete carcinogenkity in the liver and promotionpotential for tumor development in the small intestine.     

Different effects of chemicals on metabolism of N-nitrosamines in rat liver

The effects of phenobarbital (PB), 3-methylcholanthrene (MC), pyrazole (PY) and ethanol (EtOH) pretreatment on N-nitrosodimethylamine (NDMA), N-nitrosobutylmethylamine (NBMA) and N-nitrosomethylbenzylamine (NMBzA) metabolism were examined in rats. In isolated hepatocytes, PB increased the metabolic decomposition of NBMA and NMBzA, and MC increased that of NBMA; PY and EtOH increased only that of NDMA. In studies of hepatic microsomal dealkylation, PB increased NBMA debutylation and NMBzA debenzylation, and MC increased NBMA debutylation; PY and EtOH increased NDMA demethylation selectively. Several cytochrome P450 (P450) species were active in dealkylating nitrosamines, indicating that the organ-specific carcinogenicity of nitrosamines might be changed by various P450 inducers.