Human rights performance disclosure by companies having operations in high risk countries: Evidence from Australian mineral sector

The aim of this study is to explore whether Australian mineral companies operating in high human rights risk countries provide more human rights disclosures than companies operating in low risk countries. A content analysis instrument containing 88 specific human rights performance items derived from a number of international human rights guidelines has been developed to investigate the annual reports, social responsibility reports and corporate websites of the top 50 Australian mineral companies (2010/2011). The findings show that human rights performance disclosures by companies with operations in high human rights risk countries are significantly higher than companies with operations in the low risk countries. By disclosing extended human rights performance information, companies operating in high risk countries appear to ease community concerns about human rights violations. The finding is consistent with legitimacy theory which posits that organisations respond to community concerns in relation to particular social issues.

Inhibition of CYP1A2-mediated drug metabolism in vitro and in humans : With special emphasis on rofecoxib and other NSAIDs

The cytochrome P450 1A2 (CYP1A2) is one of the major metabolizing enzymes. The muscle relaxant tizanidine is a selective substrate of CYP1A2, and the non-steroidal anti-inflammatory drug (NSAID) rofecoxib was thought to modestly in-hibit it. Cases suggesting an interaction between tizanidine and rofecoxib had been reported, but the mechanism was unknown. Also other NSAIDs are often used in combination with muscle relaxants. The aims of this study were to investigate the effect of rofecoxib, several other NSAIDs and female sex steroids on CYP1A2 ac-tivity in vitro and in vivo, and to evaluate the predictability of in vivo inhibition based on in vitro data. In vitro, the effect of several NSAIDs, female sex steroids and model inhibitors on CYP1A2 activity was studied in human liver microsomes, without and with preincubation. In placebo controlled, cross-over studies healthy volunteers ingested a single dose of tizanidine after a pretreament with the inhibitor (rofecoxib, tolfenamic acid or celecoxib) or placebo. Plasma (and urine) concentrations of tizanidine and its metabolites were measured, and the pharmacodynamic effects were recorded. A caffeine test was also performed. In vitro, fluvoxamine, tolfenamic acid, mefenamic acid and rofecoxib potently in-hibited CYP1A2. Ethinylestradiol, celecoxib, desogestrel and zolmitriptan were moderate, and etodolac, ciprofloxacin, etoricoxib and gestodene were weak inhibi-tors of CYP1A2. At 100 µM, other tested NSAIDs and steroids inhibited CYP1A2 less than 35%. Rofecoxib was found to be a mechanism-based inhibitor of CYP1A2. In vivo, rofecoxib greatly increased the plasma concentrations (over ten-fold) and the pharmacodynamic effects of tizanidine. Also the metabolism of caf-feine was impaired by rofecoxib. Despite the relatively strong in vitro CYP1A2 inhibitory effects, tolfenamic acid and celecoxib did not have a significant effect on tizanidine and caffeine concentrations in humans. Competitive inhibition model and the free plasma concentration of the inhibitor predicted well the effect of fluvoxam-ine and the lack of effect of tolfenamic acid and celecoxib on tizanidine concentra-tions in humans, and mechanism-based inhibition model explained the effects of rofecoxib. However, the effects of ciprofloxacin and oral contraceptives were un-derestimated from the in vitro data. Rofecoxib is a potent mechanism-based inhibitor of CYP1A2 in vitro and in vivo. This mechanism may be involved in the adverse cardiovascular effects of rofecoxib. Tolfenamic acid and celecoxib seem to be safe in combination with tizanidine, but mefenamic acid might have some effect on tizanidine concentrations in vivo. Con-sidering the mechanism of inhibition, and using the free plasma concentration of the inhibitor, many but not all CYP1A2 interactions can be predicted from in vitro data.

The key enzyme in galactose metabolism, UDP-galactose-4-epimerase, affects cell-wall integrity and morphology in Candida albicans even in the absence of galactose

The enzyme UDP-galactose-4-epimerase (GAL10) catalyzes a key step in galactose metabolism converting UDP-galactose to UDPglucose which then can get metabolized through glycolysis and TCA cycle thus allowing the cell to use galactose as a carbon and energy source. As in many fungi, a functional homolog of GAL10 exists in Candida albicans. The domainal organization of the homologs from Saccharomyces cerevisiae and C albicans show high degree of homology having both mutarotase and an epimerase domain. The former is responsible for the conversion of beta-D-galactose to alpha-D-galactose and the hitter for epimerization of UDP-galactose to UDP-glucose. Absence of C albicans GAL10 (CaGAL10) affects cell-wall organization, oxidative stress response, biofilm formation and filamentation. Cagal10 mutant cells tend to flocculate extensively as compared to the wild-type cells. The excessive filamentation in this mutant is reflected in its irregular and wrinkled colony morphology. Cagal10 strain is more susceptible to oxidative stress when tested in presence of H2O2. While the S. cerevsiae GAL10 (ScGAL10), essential for survival in the presence of galactose, has not been reported to have defects in the absence of galactose, the C albicans homolog shows these phenotypes during growth in the absence of galactose. Thus a functional CaGal10 is required not only for galactose metabolism but also for normal hyphal morphogenesis, colony morphology, maintenance of cell-wall integrity and for resistance to oxidative stress even in the absence of galactose. (c) 2006 Elsevier Inc. All rights reserved.

Metabolism of ubiquinone in relation to vitamin a status in the rat

1. 1. Biosynthetic experiments in vitro with slices of livers from normal and vitamin A-deficient rats confirmed that synthesis of ubiquinone did not increase in vitamin A deficiency. 2. 2. During development of deficiency of vitamin A in the rat, there was a definite increase in the synthesis of ubiquinone at the 10-days stage but this reverted to low, initial level by 20 days and after. 3. 3. Vitamin A analogues, 3-dehydroretinal, 5,6-monoepoxyretinal and retinoic acid, which supported growth have restored ubiquinone concentration to the normal levels and relieved the lowering in its catabolism. The biologically inert 5,8-monoepoxyretinal was the least active of the analogues tested. 4. 4. The concentration and synthesis of ubiquinone in the liver decreased under conditions of hypervitaminosis A. 5. 5. The experimental evidence does not support the hypothesis of inverse relationship between vitamin A and ubiquinone synthesis.

Effect of cold exposure on the metabolism of ubiquinone in the rat

1. Accumulation of ubiquinone in the livers of rats exposed to a cold environment was shown to be due to both decreased catabolism during the entire experimental period and increased synthesis during an intermediate stage (10–20 days). 2. The increased endogenous synthesis in the cold-exposed rats was eliminated when ubiquinone accumulated in the liver after exposure for 40 days (coinciding with cclimatization), or by absorption of the exogenous dietary supply, possibly by the mechanism of end-product regulation.

Metabolism of Plasmodium berghei. I. Krebs cycle

The free parasites of Plasmodium berghei, obtained from infected cells of rats using an antiserum method, were investigated to study the operation of Krebs cycle. P. berghei was found to respire only with succinate; pyruvate, and other substrates of the Krebs cycle were not oxidized. The presence of a succinate dehydrogenase and a functioning cytochrome oxidase system was demonstrated. Cell-free extracts of free parasites showed the presence of enzymes for the utilization of C4 dicarboxylic acids; other enzymes of the Krebs cycle could not be detected. P. berghei differs from other species of Plasmodium in this respect.

Metabolism of Plasmodium bergheistar, open: III. Carbon dioxide fixation and role of pyruvate and dicarboxylic acids

Formation of C4 dicarboxylic acids in Plasmodium berghei by carbon dioxide fixation reaction has been demonstrated by the use of labeled NaH14CO3. The reactions require glucose, which may be required not only as an energy source but also to contribute to the formation of pyruvate in the process of carbon dioxide fixation. Intracellular concentration of pyruvate may play an important role in the metabolism of P. berghei; an increased intracellular level of pyruvate seems to be a prerequisite before some of these reactions could be detected. The distribution of the label indicates extensive randomization of amino acids and suggests an extensive cycling of the amino acid and organic acid pools of the parasites. This investigation formed part of the thesis submitted in 1965 for the doctoral degree at the Indian Institute of Science, Bangalore 12, India, and was supported in part by the Council of Scientific and Industrial Research, India.

Metabolism of Plasmodium bergheistar, open: II. 32Pi incorporation into high-energy phosphates

Free parasites of Plasmodium berghei were found to incorporate labeled inorganic phosphate into high-energy phosphates by substrate linked and oxidative hosphorylation. But the parasites also appear to utilize the reserve ATP of the host cells when they are within the host cells which may indicate the dependence of the parasite on the host cells for provision of energy. This investigation formed part of the thesis submitted in 1965 for the doctoral degree at the Indian Institute of Science, Bangalore 12, India, and was supported in part by the Council of Scientific and Industrial Research, India.

Studies on the metabolism of o-aminophenol purification and properties of isophenoxazine synthase from Bauhenia monandra

An enzyme which catalyzes the oxidative conversion of o-aminophenol to 2-amino-3-H-isophenoxazin-3-one has been purified 396-fold by using standard fractionation procedures. The enzyme is specific for o-aminophenol and has pH and temperature optima at 6.2 and 40 °, respectively. It is insensitive to metal chelating agents but is inhibited by several reducing substances. There is no cofactor or metal ion requirement for the reaction. A competitive type of inhibition was observed with structural analogs such as anthranilic acid and 3-hydroxyanthranilic acid. There are no free sulfhydryl groups in the enzyme, but preincubation of the enzyme with substrate or substrate analogs resulted in the liberation of titratable free sulfhydryl groups. The mechanism of biosynthesis of isophenoxazine ring is discussed.