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D E Cook

Publications and source records attributed to D E Cook.

At least 37 records · Page 2Linked to original sources
PubMed1983

Catalytic activities of cytochrome P-450 from female rat liver: correlation with sex differences in drug metabolism in diabetic liver.

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of detergent solubilized cytochrome P-450 fractions from normal and diabetic female rat liver microsomes revealed the induction of a 52,000 molecular weight microsomal hemeprotein in diabetic liver. Two major P-450 hemeproteins (DB IIA and DB IIB) were subsequently isolated from solubilized diabetic female rat hepatic P-450 fractions, while normal rat liver yielded only one major microsomal P-450, N IIA. When examined in a reconstituted drug metabolizing system, the aniline hydroxylation rate catalyzed by DB IIB (52,000 molecular weight) was 157% and 78% greater than the rates catalyzed by N IIA and DB IIA, respectively. The rates of ethylmorphine metabolism catalyzed by N IIA and DB IIB were similar; however, the rate of ethylmorphine metabolism catalyzed by DB IIA (54,000 molecular weight) was approximately 42% greater than the rates catalyzed by either N IIA or DB IIB. These results are compared to those previously obtained with P-450s isolated from diabetic male rat liver and indicate that diabetes induces P-450s with specific catalytic activities which can account for both the sex-dependent and sex-independent alterations in drug metabolism observed in diabetic rat liver.

Alanine↗
PubMed1982

Effect of diabetes on rat liver cytochrome P-450. Evidence for a unique diabetes-dependent rat liver cytochrome P-450.

Detergent-solubilized hepatic microsomal fractions from alloxan diabetic rats exhibited a 52,000 molecular weight hemeprotein band that was not present in the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) protein profiles of identically solubilized hepatic microsomal fractions from normal, 3-methylcholanthrene- or phenobarbital-treated rats. This 52,000 mol. wt hemeprotein band disappeared from the protein profile of insulin-treated diabetic rat liver to yield the SDS-PAGE profile of normal rat liver. When P-450 hemeproteins were purified by lauric acid affinity and hydroxylapatite chromatography from solubilized microsomes, only the diabetic rat had a 52,000 mol. wt P-450. This distinct 52,000 mol. wt diabetes-induced P-450 interacted with type II compounds to yield a 2-fold greater absorbance change than was observed with the purified P-450s from either the normal or the chemically induced rats. The properties of this unique 52,000 mol. wt P-450 suggest that it may be the catalytic component responsible for the increased rate of type II substrate (aniline) metabolism observed in the diabetic rat.

Aminopyrine↗
PubMed1982

Drug metabolism in a reconstituted system by diabetes-dependent hepatic cytochrome P-450.

Previous studies have shown that diabetes induces a unique 52,000 molecular weight cytochrome P-450 in rat hepatic microsomes. In the present study, the catalytic properties of the two major purified diabetic P-450s were contrasted to those of the major normal purified P-450 in a reconstituted drug metabolizing system. the greatest rate of aniline hydroxylation was catalyzed by the 52,000 molecular weight diabetic P-450 (7-fold greater than normal). This same diabetic P-450 also catalyzed a slower rate of ethylmorphine N-demethylation compared to the major normal and the other diabetic P-450. These results indicate that the catalytic properties of this diabetes-dependent P-450 are responsible for the substrate-specific alterations in drug metabolism observed in both liver microsomes and isolated perfused liver from diabetic rats.

Aniline Hydroxylase↗
PubMed1980

Alterations in hepatic microsomal cytochrome P-450 hemeproteins in diabetic rats.

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to determine the effect of diabetes on the cytochrome P-450-region proteins of rat liver microsomes. Compared to normal microsomes, diabetic microsomes from both male and female rats exhibited distinct increases as well as decreases in the hemeproteins of this region. These results support the concept that the substrate specific changes in drug metabolism observed in diabetic rats may be related to specific alterations in the hepatic cytochrome P-450 hemeprotein population.

Animals↗
PubMed1979

Regulation of carbohydrate metabolism in mouse liver. Effect of glucagon on gluconeogenic/glycolytic flux in isolated perfused livers.

1. Glucagon stimulated gluconeogenesis from both [U-14C]lactate and [14C]xylitol in isolated perfused mouse liver. 2. Addition of cyclic AMP also stimulated gluconeogenesis from [U-14C]lactate. 3. Glucagon caused a rapid (2.5 min) 12-fold increase in hepatic cyclic AMP but not cyclic GMP concentration. 4. Glucagon caused a rapid and stable decrease in hepatic fructose 1,6-diphosphatase activity measured in vitro. 5. The results are interpreted to indicate that glucagon stimulates hepatic gluconeogenesis in mice via cyclic AMP by two different mechanisms: (a) increased substrate uptake (i.e. utilization) and (b) increased gluconeogenic efficiency (i.e. inhibition of alternate substrate fates).

Animals↗
PubMed1979

Drug metabolism in diabetic isolated perfused rat liver.

The demethylation of aminopyrine was decreased while the demethylation of p-chloro-N-methylaniline was increased in both alloxan and streptozotocin diabetic isolated perfused male rat livers. Since similar effects of diabetes were observed with traditional microsomal preparations, these observations indicate that the effects of diabetes on drug metabolism observed in isolated microsomal preparations from male rat are an accurate reflection of conditions in the intact organ. These results also clearly indicate that diabetes in the male rat affects at least two different rate-limiting steps in the hepatic drug metabolism process.

Aminopyrine↗
PubMed1978

Effect of vasectomy on hepatic drug metabolism.

2 months after bilateral vasectomy the metabolism of aniline but not aminopyrine was increased in rat liver homogenates, whereas vasectomy did not affect the metabolism of either compound in guinea-pig liver homogenates.

Aminopyrine↗
PubMed1978

Comparison of the effects of the growth factor produced by Spirometra mansonoides and growth hormone in diabetic-hypophysectomized rats: lymphoid tissue.

Growth and development of the thymus is dependent on secretions from the anterior pituitary, presumably growth hormone. Diabetes mellitus is known to reduce immunological competence. These studies compare the effects of bovine growth hormone (bGH) and the growth factor produced by plerocercoid larvae of the tapeworm, Spirometra mansonoides, on metabolism of lymphoid tissue, thymus and spleen, in hypophysectomized rats made diabetic with a single intraperitoneal injection of alloxan. Whereas the control diabetic-hypophysectomized rats gradually lost weight throughout the experimental period, both bGH and plerocercoid infection caused significant weight gains during the experimental period. The diabetic-hypophysectomized rats treated with bGH had significantly heavier thymuses and spleens than controls. Plerocercoid infection also caused significant increases in thymus weights. Both bGH and plerocercoids stimulated the metabolic activity of thymocytes isolated from treated rats and tested for their ability to incorporate 3H-thymidine into DNA in vitro. Thus, these growth factors have similar effects on the lymphoid tissue of diabetic-hypophysectomized rats which are apparently independent of normal insulin levels. Whether this anabolic effect is direct or mediated by somatomedin remains to be determined.

Animals↗
PubMed1978

The effects of phenformin in normal vs. diabetic isolated perfused rat liver.

In the isolated perfused liver system high concentrations of phenformin (0.93--1.24 mM) were required to reduce the greater than two-fold elevated rate of gluconeogenesis from L-[U-14C]lactate in acutely alloxan diabetic (48-hour) and chronically alloxan diabetic (7-day) rat livers to the slower rate of normal fed livers. At these phenformin concentrations, other hepatic functions such as substrate uptake and 14CO2 production were also inhibited. The livers were also in a very reduced state under these conditions as indicated by the elevated ratios of the redox couples lactate/pyruvate and 3-hydroxybutyrate/acetoacetic acid. The results are interpreted to indicate that if phenformin functions as an antidiabetic (hypoglycemic) agent by inhibiting hepatic gluconeogenesis to normal levels, it is also generally toxic to the liver under such conditions. The results are discussed in relation to current hypotheses of the mechanism of action of phenformin and to phenformin-associated lactic acidosis.

Animals↗
PubMed1977

Gluconeogenesis in the guinea pig. Effect of glucagon on gluconeogenesis from lactate by isolated perfused guinea-pig liver.

Gluconeogenesis was stimulated by glucagon in fed but not fasted isolated perfused guinea pig livers. Both the amount and the rate of incorporation of radioactivity into glucose from L-[U-14C]lactate were increased in fed livers by the addition of glucagon to the perfusate. The glucagon-stimulated increase in gluconeogenesis was accompanied by an increase in oxygen consumption, an increase in the amount of lactate carbon converted to glucose and a decrease in the amount of lactate carbon converted to CO2. The results are interpreted to indicate that glucagon affects gluconeogenesis from lactate in fed livers by redirecting the fate of substrate from other products toward glucose.

Animals↗
PubMed1977

The transsulfuration pathway in Tetrahymena pyriformis.

Four enzymes necessary for the metabolism of methionine by the trans-sulfuration pathway, methionine adenosyltransferase (EC 2.5.1.6), adenosylhomocysteinase (EC 3.3.1.1), cystathionine beta-synthase (EC 4.2.1.22) and cystathionine gamma-lyase (EC 4.4.1.1) were identified in Tetrahymean pyriformis. The ability of these cells to transfer 35S from E135S]methionine to form [35S] cysteine was also observed and taken as direct evidence for the functional existence of this pathway in Tetrahymena. An intermediate in the pathway and an active methyl donor, S-adenosylmethionine, was qualitatively identified in Tetrahymena and its concentration was found to be greater in late stationary phase cells than in early stationary phase cells.

Animals↗