Allyl-containing sulfides in garlic increase uncoupling protein content in brown adipose tissue, and noradrenaline and adrenaline secretion in rats. (1/436)

The effects of garlic supplementation on triglyceride metabolism were investigated by measurements of the degree of thermogenesis in interscapular brown adipose tissue (IBAT), and noradrenaline and adrenaline secretion in rats fed two types of dietary fat. In Experiment 1, rats were given isoenergetic high-fat diets containing either shortening or lard with or without garlic powder supplementation (8 g/kg of diet). After 28 d feeding, body weight, plasma triglyceride levels and the weights of perirenal adipose tissue and epididymal fat pad were significantly lower in rats fed diets supplemented with garlic powder than in those fed diets without garlic powder. The content of mitochondrial protein and uncoupling protein (UCP) in IBAT, and urinary noradrenaline and adrenaline excretion were significantly greater in rats fed a lard diet with garlic powder than in those fed the same diet without garlic. Other than adrenaline secretion, differences due to garlic were significant in rats fed shortening, also. In Experiment 2, the effects of various allyl-containing sulfides present in garlic on noradrenaline and adrenaline secretion were evaluated. Administration of diallyldisulfide, diallyltrisulfide and alliin, organosulfur compounds present in garlic, significantly increased plasma noradrenaline and adrenaline concentrations, whereas the administration of disulfides without allyl residues, diallylmonosulfide and S-allyl-L-cysteine did not increase adrenaline secretion. These results suggest that in rats, allyl-containing sulfides in garlic enhance thermogenesis by increasing UCP content in IBAT, and noradrenaline and adrenaline secretion.  (+info)

Cytochrome P-450-dependent bioactivation of 1,1-dichloroethylene to a reactive epoxide in human lung and liver microsomes. (2/436)

We investigated the cytochrome P-450-dependent metabolism of 1, 1-dichloroethylene (DCE) by human lung and liver microsomes and compared the results from analogous experiments in mice. Metabolites were identified by HPLC analysis of their glutathione conjugates and/or hydrolyzed products and were detected by using [14C]DCE. The role of human CYP2E1 in the metabolic reactions was examined by comparing p-nitrophenol hydroxylase activities with levels of metabolites formed and by using the CYP2E1-selective inhibitor diallyl sulfone. The major products formed in microsomal incubations containing NADPH were the DCE-epoxide-derived glutathione conjugates 2-(S-glutathionyl)acetyl glutathione and 2-S-glutathionyl acetate. Lower levels of the acetal of 2,2-dichloroacetaldehyde were also detected. In lung samples from eight patients, the amounts of epoxide-derived conjugates formed ranged from 15.6 +/- 4.23 to 34.9 +/- 12.75 pmol/mg protein/min. The levels in murine lung were higher at 40.0 +/- 3.8 pmol/mg protein/min. In liver samples from five patients, conjugate levels ranged from 46.5 +/- 8.3 to 240.0 +/- 10. 5 pmol/mg protein/min, whereas levels in murine liver were 83.0 +/- 6.2 pmol/mg protein/min. Conjugate levels formed in human liver correlated with the relative levels of p-nitrophenol hydroxylase activity present, but this relationship was equivocal in human lung. Diallyl sulfone inhibited the formation of the glutathione conjugates (20-65%) in liver samples from all four patients, whereas only one of five human lung samples exhibited this inhibition (27%). These results demonstrated that the DCE-epoxide is a major metabolite formed by human microsomes and is mediated by CYP2E1 in liver and in some individuals in lung.  (+info)

Inhibition of nitrifiers and methanotrophs from an agricultural humisol by allylsulfide and its implications for environmental studies. (3/436)

Allylsulfide, an inhibitor of ammonia monooxygenase, was tested to determine its ability to inhibit nitrification and methane oxidation in pure cultures, in agricultural humisol enrichment cultures, and in humisol slurries. We confirmed that allylsulfide is a differential inhibitor of cultures of nitrifiers and methanotrophs at concentrations of 1 and 200 microM, respectively, which result in 50% inhibition. However, although a nitrifying enrichment culture added to sterilized humisol was inhibited 50% by 4 microM allylsulfide, 500 microM allylsulfide was necessary for 50% inhibition of the endogenous nitrifying activity in nonsterile humisol. We concluded that native nitrifiers were protected, possibly by being in colonial aggregates or sheltered microenvironments.  (+info)

Metabolism of diallyl disulfide by human liver microsomal cytochromes P-450 and flavin-containing monooxygenases. (4/436)

The metabolism of diallyl disulfide (DADS), a garlic sulfur compound, was investigated in human liver microsomes. Diallyl thiosulfinate (allicin) was the only metabolite observed and its formation followed Michaelis-Menten kinetics with a Km = 0.61 +/- 0.2 mM and a Vmax = 18.5 +/- 4.2 nmol/min/mg protein, respectively (mean +/- S.E. M., n = 4). Both flavin-containing monooxygenase and the cytochrome P-450 monooxygenases (CYP) were involved in DADS oxidation, but the contribution of CYP was predominant. The cytochrome P-450 isoforms involved in this metabolism were investigated using selective chemical inhibitors, microsomes from cells expressing recombinant CYP isoenzymes, and studying the correlation of the rate of DADS oxidation with specific monooxygenase activities of human liver microsomes. Diethyldithiocarbamate and tranylcypromine inhibited allicin formation, whereas other specific inhibitors had low or no effect. Most of the different human microsomes from cells expressing CYP were able to catalyze this reaction, but CYP2E1 showed the highest affinity with a substantial activity. Furthermore, allicin formation by human liver microsomes was correlated with p-nitrophenol hydroxylase activity, a marker of CYP2E1, and tolbutamide hydroxylase activity, a marker of CYP2C9. Among these approaches only CYP2E1 was identified in each case, which suggested that DADS is preferentially metabolized to allicin by CYP2E1 in human liver. However the minor participation of other CYP forms and flavin-containing monooxygenases is likely.  (+info)

In vivo formation and localization of 1,1-dichloroethylene epoxide in murine liver: identification of its glutathione conjugate 2-S-glutathionyl acetate. (5/436)

The hepatotoxic effects induced by 1,1-dichloroethylene (DCE) are ascribed to cytochrome P-450 (CYP) 2E1-dependent formation of metabolites including 2,2-dichloroacetaldehyde and the DCE-epoxide. The DCE metabolites detected in incubations of liver microsomes are the acetal, the hydrate of 2,2-dichloroacetaldehyde, and the epoxide-derived GSH conjugates 2-S-glutathionyl acetyl glutathione ([B]) and 2-S-glutathionyl acetate ([C]). This study was undertaken to determine whether these DCE metabolites are also formed in vivo in murine liver. HPLC analysis of cytosol isolated from the livers of mice treated with [(14)C]DCE showed that [C] was the major conjugate formed, with lower levels of formation of [B]. The acetal was not detected in the cytosol. The formation of the epoxide-derived GSH conjugates was dose-dependent at 25 to 225 mg/kg DCE and occurred coincidentally with levels of covalent binding of DCE at the same doses. The acetal and conjugates [B] and [C] were also detected in bile collected from mice treated with DCE. Pretreatment of mice with buthionine sulfoximine decreased sulfhydryl levels and formation of conjugate [C], and increased DCE binding to liver proteins. In contrast, the levels of [C] and DCE binding were both reduced significantly in mice pretreated with the CYP2E1 inhibitor diallyl sulfone. Immunohistochemical studies indicated that protein adducts and conjugate [C] were localized in centrilobular hepatocytes and corresponded with the sites where CYP2E1 resided. Pretreatment with buthionine sulfoximine increased the amount of immunostaining. However, pretreatment with diallyl sulfone markedly decreased immunostaining for [C] in the hepatocytes. These results showed that 2,2-dichloroacetaldehyde and the epoxide are formed from DCE in vivo.  (+info)

Effects of allitridi on intracellular Ca2+ concentration in isolated rat brain cells. (6/436)

AIM: To study actions of allitridi extracted from garlic on intracellular calcium in isolated rat brain cells. METHODS: Brain cells were isolated from newborn rat brain with Fura 2-AM measurements of intracellular Ca2+ concentration ([Ca2+]i). RESULTS: Allitridi 1-100 mumol.L-1 concentration-dependently blocked increases of [Ca2+]i caused by potassium chloride and sodium glutamate (Glu) with IC50 of 59.7 and 69.9 mumol.L-1 respectively. Allitridi 100 mumol.L-1 blocked norepinephrine (Nor)-induced [Ca2+]i elevation. CONCLUSION: Allitridi is an effective agent for blocking the [Ca2+]i increase caused by potassium chloride, Nor and Glu.  (+info)

Roles of horizontal gene transfer and gene integration in evolution of 1,3-dichloropropene- and 1,2-dibromoethane-degradative pathways. (7/436)

The haloalkane-degrading bacteria Rhodococcus rhodochrous NCIMB13064, Pseudomonas pavonaceae 170, and Mycobacterium sp. strain GP1 share a highly conserved haloalkane dehalogenase gene (dhaA). Here, we describe the extent of the conserved dhaA segments in these three phylogenetically distinct bacteria and an analysis of their flanking sequences. The dhaA gene of the 1-chlorobutane-degrading strain NCIMB13064 was found to reside within a 1-chlorobutane catabolic gene cluster, which also encodes a putative invertase (invA), a regulatory protein (dhaR), an alcohol dehydrogenase (adhA), and an aldehyde dehydrogenase (aldA). The latter two enzymes may catalyze the oxidative conversion of n-butanol, the hydrolytic product of 1-chlorobutane, to n-butyric acid, a growth substrate for many bacteria. The activity of the dhaR gene product was analyzed in Pseudomonas sp. strain GJ1, in which it appeared to function as a repressor of dhaA expression. The 1,2-dibromoethane-degrading strain GP1 contained a conserved DNA segment of 2.7 kb, which included dhaR, dhaA, and part of invA. A 12-nucleotide deletion in dhaR led to constitutive expression of dhaA in strain GP1, in contrast to the inducible expression of dhaA in strain NCIMB13064. The 1, 3-dichloropropene-degrading strain 170 possessed a conserved DNA segment of 1.3 kb harboring little more than the coding region of the dhaA gene. In strains 170 and GP1, a putative integrase gene was found next to the conserved dhaA segment, which suggests that integration events were responsible for the acquisition of these DNA segments. The data indicate that horizontal gene transfer and integrase-dependent gene acquisition were the key mechanisms for the evolution of catabolic pathways for the man-made chemicals 1, 3-dichloropropene and 1,2-dibromoethane.  (+info)

Ethanol and arachidonic acid increase alpha 2(I) collagen expression in rat hepatic stellate cells overexpressing cytochrome P450 2E1. Role of H2O2 and cyclooxygenase-2. (8/436)

The ability of ethanol and arachidonic acid (AA), as inducers of oxidative stress and key factors in alcoholic liver disease, to up-regulate alpha 2 collagen type I (COL1A2) gene expression was studied in a hepatic stellate cell line overexpressing the ethanol-inducible cytochrome P450 2E1 (CYP2E1) (E5 cells). A time- and dose-dependent induction in COL1A2 mRNA by ethanol or AA was observed that was prevented by diallylsulfide, a CYP2E1 inhibitor. Nuclear run-on experiments showed transcriptional activation of the COL1A2 gene by ethanol and AA. Catalase abrogated the increase in COL1A2 mRNA suggesting an H(2)O(2)-dependent mechanism. Cyclooxygenase-2 (COX-2) levels and production of prostaglandin E(2) upon addition of AA were elevated in the E5 cells. Incubation with NS-398, a COX-2 inhibitor, blocked the effect of AA, but not of ethanol, on COL1A2 expression suggesting that CYP2E1 activates COX-2 expression, and the oxidation of AA by COX-2 is responsible for the increase in COL1A2. Activity of a reporter construct driven by -378 base pairs of the proximal promoter region of the COL1A2 gene increased in E5 but not control cells and was further increased by ethanol or AA. These experiments link CYP2E1-dependent oxidative stress to induction of COX-2 and the actions of ethanol and AA on activation of collagen gene expression in hepatic stellate cells.  (+info)

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