Characterization of enzymes responsible for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) detoxification pathway in lungs of Chinese population: Carbonyl reduction and glucuronidation

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent carcinogens found in mainstream and sidestream smoke and considered to be a causative agent for lung cancer in active and passive smokers. Carbonyl reduction followed by glucuronidation is considered to be the main detoxification pathway of NNK. Microsomal 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD 1) and cytosolic carbonyl reductase (CR) are responsible for NNK carbonyl reduction, and UDP-glucuronosyltransferase 1A4 (UGT1A4) and UDP-glucuronosyltransferase 2B7 (UGT2B7) catalyze 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) glucuronidation. To better characterize this pathway, the expression and kinetics of 11β-HSD 1 and CR, as well as the expression of UGT1A4 and UGT2B7, was investigated in lungs of Chinese people. Kinetic studies for 11β-HSD 1 and CR showed that there was large inter-individual variability in the capacity for NNK carbonyl reduction. Compared with cytosol, there was increased catalytic efficiency for NNAL formation in microsomes. The higher activities of both 11β-HSD 1 and CR were observed in lung tissues of males than females. UGT1A4 and UGT2B7 mRNA were detected in lungs from a variety of different patients and wide inter-individual variations were observed. These observations should be useful in improving the risk estimates and prevention of lung cancer for the Chinese population exposed to tobacco smoke.     

Impaired phospholipid metabolism in Saccharomyces cerevisiae by increased phospholipase B activity induced by 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone

Tobacco products and cigarette smoke cause many respiratory diseases including cancer. 4-(Methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen in cigarette smoke, but its effect on lipid metabolism remains enigmatic. Hence, Saccharomyces cerevisiae was exposed to different concentrations of NNK (0–400?µmol?L^?1) to elucidate its role in lipid metabolism. Exposure to NNK substantially decreases (about 60%) of the phospholipid content with a concomitant increase in lysophospholipids. Significant reduction was observed in the phosphatidylcholine followed by phosphatidylethanolamine with NNK-treated cells. On the contrary, cells accumulated significant amount of neutral lipids and free fatty acids. Exposure of yeast cells (wild-type cells and three plbΔ mutant strains) to NNK greatly enhances the hydrolysis of phospholipid in the presence of calcium. We are the first to report that exposure to NNK enhances phospholipase B (PLB), particularly plb1p activity. Furthermore, NNK also promotes the alteration of phospholipid fatty acid (FA) content. These results suggest that NNK aids in the degradation of phospholipids by enhanced PLB activity and is accompanied with FA alteration. Understanding the altered phospholipid metabolism in the presence of NNK remains a worthy pursuit.     

Hepatoprotective activity of 1-(4-(Dimethylamino)Benzylidene)-5-(2-Oxoindolin-3-ylidene) Thiocarbohydrazone in rats

The aim of the present study was to evaluate the hepatoprotective activity of 1-(4-(dimethylamino)benzylidene)-5-(2-oxoindolin-3-ylidene) thiocarbohydrazone, a novel isatin derivative against carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Hepatic damage was induced by administration of CCl₄ (1 ml/kg, b.w., p.o.) in combination with liquid paraffin (1:1) as a single dose. The hepatotoxic rats were treated with test compound at doses of 50 or 100 mg/kg for three days and liver damage biomarkers, including activities of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), serum alkaline phosphatase (ALP), and levels of total serum bilirubin (TB) measured in blood samples. Results demonstrated that treatment with test compound at doses of 50 or 100 mg/kg to hepatotoxic rats produced a significant dose-dependent reduction of elevated SGOT, SGPT, ALP activities and TB levels indicating a hepatoprotective effect that was confirmed by histopathological examination of liver tissues. The study results confirmed the hepatoprotective activity of 1-(4-(dimethylamino)benzylidene)-5-(2-oxoindolin-3-ylidene) thiocarbohydrazone in rats.     

Synthesis of some novel (2-oxo-3-(arylimino) indolin-1-yl)-N-aryl acetamides and evaluation as antimicrobial agents

A series of sixteen 2-oxo-3-(arylimino) indolin-1-yl)-N-aryl acetamide derivatives were synthesized, characterized by physical and spectral data (IR, ¹H nuclear magnetic resonance (NMR), and mass spectrometry), and evaluated for their antibacterial and antifungal activities against various pathogenic microorganisms. Some of the synthesized compounds showed promising antibacterial and antifungal activities, the best being 2-(3-(4-chlorophenylimino)-2-oxoindolin-1-yl)-N-(3-methoxyphenyl) acetamide.     

Microbiological evaluation of 4-(6-chloro-7H-purin-8-ylamino)-3-nitro-chromen-2-one with a comparison to antibacterial activity of standard drugs

Nucleophilic substitution of 4-chloro-3-nitro-2-oxo-2H-chromen-2-one 3 by 6-chloro-7H-purin-2-ylamine (a), yielded the corresponding 4-(6-chloro-7H-purin-8-ylamino)-3-nitro-chromen-2-one 4. The chemical structure of synthesized compound was characterized using IR and NMR spectra, and elemental analyses. The purified synthesized compound 4 was tested at concentrations 1, 3, 5 mg/ml for its antibacterial activity against three bacterial cultures: Staphylococcus aureus, Escherichia coli, and Bacillus cereus. The antibacterial activity of synthesized compound was compared to antibacterial activity of standard antibiotics cephalexine and streptomycin.