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C R Barnett

Publications and source records attributed to C R Barnett.

At least 19 recordsLinked to original sources
PubMed1992

Cytochrome P-450-dependent mixed-function oxidase and glutathione S-transferase activities in spontaneous obesity-diabetes.

The effect of non-insulin-dependent diabetes on the hepatic microsomal cytochrome P450-dependent mixed-function oxidase system and on cytosolic glutathione S-transferase activity was determined using the spontaneously obese-diabetic (ob/ob) mouse model. The activities of the xenobiotic-metabolizing cytochrome P450 proteins were monitored by the use of chemical probes. Non-insulin-dependent diabetes did not influence the hepatic metabolism of substrates associated with the P450 I, IIB, IIE, III and IV families of cytochromes. In contrast, cytosolic glutathione S-transferase activity was markedly reduced and glutathione levels were significantly lowered. These findings raise the possibility that patients suffering from this disease may be more susceptible to chemicals that rely on glutathione conjugation for their deactivation.

Animals↗
PubMed1992

Hyperinsulinaemia causes a preferential increase in hepatic P4501A2 activity.

Male NEDH (New England Deaconess Hospital) rats were transplanted with a radiation-induced tumour from a donor male rat and were killed 18 days following transplantation. At the time of killing the insulinoma-bearing animals were severely hypoglycaemic but plasma ketone levels were normal. Insulinoma-bearing animals exhibited higher hepatic O-deethylation of ethoxyresorufin and N-demethylation of ethylmorphine activities when compared to control animals. Similarly, hepatic microsomal preparations from insulinoma-bearing rats were more efficient than control animals in converting the promutagen 2-amino-6-methyldipyrido[1,2-a:3',2']imidazole (Glu-P-1) to mutagenic intermediates in the Ames test. Immunoblot analysis employing polyclonal antibodies against the P4501A and P453A families revealed that insulinoma-bearing rats had higher hepatic P4501A2 apoprotein levels. No major differences in P4503A1 apoprotein levels between insulinoma-bearing and control rats were noted. Subcutaneous administration of insulin to male Wistar rats gave rise to a modest increase in ethoxyresorufin O-deethylase activity and in the ability to activate Glu-P-1 to mutagens in the Ames test. Immunoblot analysis revealed an increase in hepatic P4501A2 apoprotein levels following the treatment with insulin. It is concluded that insulinoma-bearing rats display high P4501A2 activity and the hyperinsulinaemia that characterize this condition is responsible for the effect. Moreover, administration of insulin to other strains of rat, such as Wistar, also enhances P4501A2 activity, presumably as a result of hyperinsulinaemia.

Animals↗
PubMed1992

Induction of rat hepatic mixed-function oxidases by acetone and other physiological ketones: their role in diabetes-induced changes in cytochrome P450 proteins.

1. To evaluate the role of ketone bodies in diabetes-induced changes in hepatic cytochrome P450 composition, rats were treated with acetone, 3-hydroxybutyrate or 1,3-butanediol. 2. Treatment with acetone enhanced the rat hepatic O-dealkylations of ethoxyresorufin and methoxyresorufin, and the hydroxylation of p-nitrophenol, but had no effect on lauric acid hydroxylation and ethylmorphine N-demethylation. Neither 3-hydroxybutyrate nor 1,3-butanediol modulated the metabolism of the above substrates. 3. Immunoblot analysis of hepatic microsomal proteins revealed that treatment with acetone increased the apoprotein levels of P4501A2, P4502B1/2 and P4502E1. 4. It is concluded that acetone is responsible, at least partly, for the diabetes-induced increase in hepatic microsomal P4501A2, P4502B1/2 and P4502E1 proteins but does not mediate the increases in the P4503A1 and P4504A1 proteins. On the basis of work from our own and other laboratories a mechanism for the diabetes-induced changes in hepatic cytochrome P450 proteins is proposed.

Acetone↗
PubMed1990

Induction of cytochrome P450III and P450IV family proteins in streptozotocin-induced diabetes.

The effect of insulin-dependent diabetes on the hepatic microsomal activity of cytochrome P450III and P450IV family proteins was investigated in rats pretreated with streptozotocin. In order to discern between the effects of the diabetogen per se and those of the ensuing diabetes, streptozotocin-treated rats received in addition either nicotinamide to prevent the onset of diabetes or daily treatment with insulin to antagonize the effects of diabetes. Streptozotocin-treated rats displayed higher ethylmorphine and erythromycin N-demethylase activities and lauric acid hydroxylase activity. Increases were also detected immunologically by using monospecific polyclonal antibodies against the P450III and P450IV families. All effects were prevented by nicotinamide and effectively antagonized by insulin. In order to evaluate the role of the ketone bodies in the diabetes-induced increases in the above activities, rats were rendered hyperketonaemic by dietary administration of medium-chain triacylglycerols. These hyperketonaemic animals displayed high laurate hydroxylase activity and P450IV apoprotein levels, similar to those seen in the diabetic animals. Hyperketonaemia induced by dietary means caused a modest increase in the demethylation of erythromycin and had no significant effect on the N-demethylation of ethylmorphine. Furthermore, no marked increases were evident in the P450III apoprotein levels in the hyperketonaemic animals. It is concluded that insulin-dependent diabetes induces proteins of the P450III and P450IV families, and that the hyperketonaemia that accompanies diabetes is largely responsible for the changes in the latter family.

Animals↗
PubMed1990

Hyperketonaemia markedly modulates the metabolic activation of chemical carcinogens.

Male Wistar albino rats were rendered hyperketonaemic by oral administration of medium chain triacylglycerols or by a single intraperitoneal injection of the diabetogenic agent streptozotocin. Hepatic post-mitochondrial preparations from these animals were employed as activation systems in the Ames mutagenicity test. Activation systems from both groups of hyperketonaemic rats were more efficient than those of control rats in metabolically converting the precarcinogens Glu-P-1, Trp-P-1, Trp-P-2, N-nitrosopiperidine and N-nitrosopyrrolidine to mutagens. In contrast, when 2-aminofluorene was used as the precarcinogen, the preparations from the hyperketonaemic animals were less efficient than controls in activating this carcinogen. In all cases, the preparations from streptozotocin-treated rats displayed a more pronounced effect than those from triacylglycerol-treated rats, possibly reflecting the greater extent of hyperketonaemia in the former group. It is concluded that hyperketonaemia modulates the bioactivation of chemical carcinogens.

3-Hydroxybutyric Acid↗
PubMed1990

Transient postoperative blindness as a possible effect of glycine toxicity.

This case report of transient blindness after bilateral knee arthroscopy postulates glycine toxicity as a possible cause of postoperative blindness. The orthopaedic surgeon should be aware of this dose-related effect, and should use glycine irrigant selectively and sparingly for electrosurgical applications.

Arthroscopy↗
PubMed1989

Induction of the rat hepatic microsomal mixed-function oxidases by cimetidine.

The ability of cimetidine to induce the hepatic microsomal mixed-function oxidases was investigated in rats treated orally with the drug at 3 dose levels: 10, 100 and 500 mg/kg. At the highest dose only, cimetidine stimulated the dealkylations of ethoxyresorufin, ethoxycoumarin and pentoxyresorufin but inhibited that of erythromycin and had no effect on the demethylation of dimethylnitrosamine. At the highest dose cimetidine had a small effect on the activation of Glu-P-1 to mutagens in the Ames test but induced proteins recognised in Western blots by antibodies to P450 I A1 and P450 II B1. It is concluded that cimetidine is a weak selective inducer of cytochrome P-450 forms, but at therapeutic doses its inductive effect is most unlikely to be of any clinical or toxicological consequence.

Animals↗
PubMed1988

Role of ketone bodies in the diabetes-induced changes in hepatic mixed-function oxidase activities.

In order to assess the role of ketone bodies in the diabetes-induced changes in hepatic mixed-function oxidase activity, rats rendered hyperketonaemic by dietary administration of medium chain triacylglycerols were compared with streptozotocin treated rats. Both groups of animals became hyperketonaemic but only the latter were hyperglycaemic. Treatment with streptozotocin or medium chain triacylglycerols gave rise to marked increases in the O-dealkylations of ethoxyresorufin, ethoxycoumarin and pentoxyresorufin, the p-hydroxylation of aniline and the N-demethylation of dimethylnitrosamine. It is concluded that the streptozotocin-induced changes in hepatic mixed-function oxidases are mediated, at least partly, by the high levels of ketone bodies.

Animals↗