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Biomedical subjects

D V Parke

Publications and source records attributed to D V Parke.

At least 145 records · Page 8Linked to original sources
PubMed1981

Bifluranol, a novel fluorinated bibenzyl anti-androgen, its chemistry and disposition in different animal species.

The synthesis of bifluranol, a new fluorinated bibenzyl anti-androgen, and of 3H-labelled bifluranol is described. The absorption, distribution and excretion of bifluranol has been studied in mouse, rat, ferret and dog; it is readily absorbed following oral administration, but blood concentrations of the drug are low due to hepatic uptake and biliary excretion. Enterohepatic re-circulation occurs, but the drug is excreted primarily in the faeces and only small amounts appear in urine. This pattern of disposition and excretion is similar to that reported elsewhere for the bibenzyl, hexoestrol, and for the stilbene, diethylstilboestrol.

Administration, Oral↗
PubMed1981

The metabolism of bifluranol by rat, dog and ferret.

The synthesis of monohydroxy- and dihydroxy-bifluranol, and of glucuronide and sulphate conjugates of bifluranol are described. Bifluranol administered orally to rats, ferrets and dogs at a dosage of 50 to 200 microgram kg-1 is mostly excreted in the faeces as unchanged bifluranol and bifluranol monosulphate, disulphate and monoglucuronide. The bifluranol is well absorbed and is mostly excreted in the bile, as six different conjugates, including a glucuronide sulphate found in all 3 species, and a glucuronide phosphate found only in ferret and dog bile. Hydroxylation of the aromatic rings occurs in the rat, to an extent of about 8% of the dose, but was not detected in ferret or dog.

Animals↗
PubMed1981

Activation of benzo(a)pyrene and 2-acetamidofluorene to mutagens by microsomal preparations from different animal species: role of cytochrome P-450 and P-448.

1. The metabolic activation of benzo(a)pyrene and 2-acetamidofluorene to mutagens was studied with liver microsomal preparations from rat, guinea-pig, hamster and mouse, untreated or pretreated with phenobarbitone or 3-methylcholanthrene. 2. Liver microsomal preparations from all animal species activated benzo(a)pyrene, that from mouse being the most efficient. Similarly, microsomal preparations from guinea-pig, hamster and mouse could activate 2-acetamidofluorene, but that from rat exhibited very weak activity. 3. Activation of benzo(a)pyrene into mutagenic intermediates by liver microsomal preparations was increased for all animals except mouse by pretreatment with 3-methylcholanthrene. In contrast, pretreatment with phenobarbitone decreased the activation by microsomal preparations from all species. 4. Activation of 2-acetamidofluorene by liver microsomal preparations from rat and guinea-pig, but not mouse and hamster, was increased by pretreatment of the animals with phenobarbitone. Pretreatment with 3-methylcholanthrene decreased the activation of this carcinogen by microsomal preparations from all species. 5. The metabolic activation of benzo(a)pyrene is catalysed by cytochrome P-448 but not cytochrome P-450. 6. The activation of 2-acetamidofluorene to mutagens may involve, in addition to the mixed-function oxidases, other microsomal enzyme systems.

2-Acetylaminofluorene↗
PubMed1980

Prealbumin as an index of liver function after acute paracetamol poisoning.

Liver damage in a woman who had taken an overdose of paracetamol and dextropropoxyphene was assessed by monitoring serum prealbumin concentrations and by routine plasma enzyme determinations. The plasma aspartate aminotransferase returned to normal levels after 3 days, alkaline phosphatase was slow to show increases in activity, and serum albumin concentration was in the normal range throughout. Prothrombin-time, although initially very high, returned almost to normal as a result of the administration of plasma. In contrast, serum prealbumin concentration decreased significantly after 36 h and continued to decrease, showing the course of failing liver function, until the patient's death 15 days after presentation. Prealbumin, a functional plasma protein synthesised in the liver, has a short half-life, is a true index of liver function, and seems to be a more reliable indicator of liver function in drug overdose than plasma enzymes, prothrombin-time, or plasma drug concentration.

Acetaminophen↗
PubMed1980

The metabolic oxidation of the ethynyl group in 4-ethynylbiphenyl in vitro.

1. The metabolism of 4-ethynylbiphenyl has been studied in vitro with subcellular fractions of normal and induced rat liver, and rat intestinal microflora (caecal contents). 2. Oxidation was NADPH-dependent, was inhibited by CO and stimulated by pretreatment with phenobarbitone or 3-methylcholanthrene. 3. Oxidation of the ethynyl group occurred in washed microsomal preparations, but not significantly in soluble fractions. Oxidation of the ethynyl group by a microsomal fraction preceded aromatic hydroxylation and no metabolites containing the intact ethynyl group were detected. 4. The major metabolite in liver fractions was biphenyl-4-ylacetic acid. This was the only product produced by a modified Udenfriend system. 5. Metabolism of 4-ethynylbiphenyl by rat caecal contents under anaerobic conditions produced very small amounts of 4-vinylbiphenyl. 6. In a modified Ames test with Salmonella typhimurium TA98, 4-ethynylbiphenyl gave a weak positive result that was doubled after 'activation' with an induced rat S9 fraction.

Acetylene↗
PubMed1980

The effects of carbon disulphide on rat liver microsomal mixed-function oxidases, in vivo and in vitro.

An intraperitoneal dose of CS(2) (500mg/kg) to male rats resulted in loss of liver microsomal mixed-function-oxidase activity (85% loss of biphenyl 4-hydroxylase), followed by denaturation of liver cytochrome P-450 to cytochrome P-420, and degradative loss of both cytochromes (50% loss). Losses of NADPH-cytochrome c reductase (20%) and cytochrome b(5) were considerably less. Intraperitoneal administration of CS(2) (100mg/kg) to rats pretreated wtih phenobarbitone or 3-methylcholanthrene resulted in similar losses, but the rate of destruction was greater with cytochrome P-450 than with cytochrome P-448. At 12h after intraperitoneal injection of CS(2) to non-pretreated rats, a new cytochrome (P-448) appeared. Rat liver microsomal preparations incubated with CS(2) in the presence of NADPH and O(2) resulted in loss of cytochrome P-450 and mixed-function-oxidase activity directly related to the concentration of CS(2) (10-100mum) and to the period of incubation. Addition of EDTA (1mm) completely inhibited this destruction of cytochrome P-450 by CS(2)in vitro. Addition of CS(2) to liver microsomal preparations resulted in moderate increases in the K(s) values for type-I or type-II substrates, but these were insufficient to account for the inhibition of the mixed-function oxidases. We therefore suggest that desulphuration of CS(2) leads to binding of the S to cytochrome P-450, denaturation of cytochrome P-450 to cytochrome P-420, and ultimately to destruction of these cytochromes by autoxidation.

Animals↗
PubMed1980

Ligand binding of safrole to cytochrome P-450.

Safrole, a hepatocarcinogen, is converted by the microsomal mono-oxygenase system to a reactive intermediate which interacts with cytochrome P-450 to form a ligand complex. The formation of this complex is accompanied by loss of mono-oxygenase activity. The present study describes the interaction of the safrole reactive intermediate with microsomes from phenobarbital, 3-methylcholanthrene and safrole pretreated animals.

Animals↗
PubMed1980

Inhibition of cytochrome P-448 mixed function oxidase activity following administration of 9-hydroxyellipticine to rats.

The in vitro inhibitor of mixed-function oxidation, 9-hydroxyellipticine, non-competitively inhibited the binding of the type II substrate, aniline, to cytochrome P-448 of hepatic microsomal preparations from rats pretreated with 3-methylcholanthrene. In contrast, 9-hydroxyellipticine did not inhibit the binding of aniline to cytochrome P-450 of hepatic microsomal preparations from rats pretreated with phenobarbitone, nor did it inhibit the binding of the type I substrate, hexobarbitone to either cytochrome P-450 or cytochrome P-448. Following the pretreatment of rats intraperitoneally with 9-hydroxyellipticine and phenobarbitone, the cytochrome P-448-specific enzyme activity, ethoxyresorufin O-deethylase, was 50% inhibited in vitro but cytochrome P-450, cytochrome P-450 reductase, and other mixed function oxidase activities were unaffected. With rats pretreated with 9-hydroxyellipticine and 3-methylcholanthrene, inhibition of ethoxyresorufin O-deethylase was 90%, and cytochrome P-450/P-448, cytochrome P-450 reductase, biphenyl 2- and 4-hydroxylase were inhibited by 30, 15, 50 and 40% respectively. It is concluded that 9-hydroxyellipticine administered in vivo markedly inhibits mixed-function oxidations which are specific to cytochrome P-448, but has no effect on cytochrome P-450-catalysed microsomal oxidation.

Alkaloids↗
PubMed1980

Cadmium-induced reduction of bone alkaline phosphatase and its prevention by zinc.

The dietary exposure of rats to cadmium (75 ppm) for periods of up to 48 weeks caused an accumulation of cadmium in the femur, and an inhibition of the accumulation of zinc in the bone. After 48 weeks of cadmium treatment, there was a decreased activity of alkaline phosphatase in the femur. This effect was prevented by a simultaneous dietary supplement of zinc (300 ppm).

Alkaline Phosphatase↗
PubMed1980

The urinary excretion of alkaline phosphatase after the repeated parenteral administration of cadmium to rats given a high dietary supplement of zinc.

Repeated parenteral administration of cadmium (Cd) (1.5 mg Cd2+/kg, daily for 28 days) produced an initial transitory (< 4 days) increase in the urinary excretion of alkaline phosphatase within 48 h: a second and persistent phase of enzymuria developed around day 15. Pretreatment and simultaneous administration of zinc (Zn) as a dietary supplement (2000 ppm Zn2+) abolished the initial phase of enzymuria but had no effect upon the second phase.

Alkaline Phosphatase↗
PubMed1980

The effect of dietary cadmium on zinc, copper and iron levels in the bone of rats.

The effect of continuous oral administration of cadium (Cd) (75 ppm) on the concentrations of zinc (ZN), Copper (CU) and iron (Fe) in the bone of rats was investigated. Accumulation of Cd in the femur was low but increased with time. After 8 weeks of Cd exposure, femur Zn and Fe levels were significantly decreased and remained low throughout the period of cadmium treatment. After 48 weeks, Cd exposed animals had Zn and Fe concentrations in the femur of 63% and 51% of controls, respectively. The femur Cu concentration was unchanged at 36 weeks but at 48 weeks it was 76% of control animals.

Animals↗
PubMed1980

Activation of hepatic microsomal biphenyl 2-hydroxylation by corticosteroids.

1. 4-Hydroxylation was a major route of biphenyl metabolism in liver microsomes from control and phenobarbitone-pretreated rats, with 2- and 3-hydroxybiphenyl as lesser metabolites. 2. Many corticosteroids, when added to the microsomal incubation mixture, selectively increased 2-hydroxylation with little or no effect on 3- and 4-hydroxylation. Betamethasone caused the greatest activation (400%). 3. In liver microsomes from controls hamsters and 3-methylcholanthrene-pretreated rats, the basal hydroxylase activity, especially 2-hydroxylation, was much higher, but the quantitative increase following betamethasone addition was similar to that in liver microsomes from control and phenobarbitone-pretreated rats. 4. Pretreatment of rats with betamethasone also resulted in a small increase in biphenyl 2-hydroxylation activity after 4 h, returning to control values after 6 h. 5. In vitro addition of estradiol or testosterone had no effect on either basal or betamethasone-activated biphenyl 2-hydroxylation.

Adrenal Cortex Hormones↗