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Biomedical subjects

R W Chadwick

Publications and source records attributed to R W Chadwick.

At least 37 records · Page 2Linked to original sources
PubMed1986

Use of gamma-hexachlorocyclohexane (lindane) to determine the ontogeny of metabolism in the developing rat.

The compound lindane (gamma-hexachlorocyclohexane) has been used to study the ontogeny of metabolism in the developing Fischer 344 rat. The distribution and metabolic fate of lindane at 2, 9, 16, and 23 d of age was investigated following subcutaneous administration of lindane at 20 mg/kg containing 0.5 microCi [U-14C]lindane in peanut oil. Groups of 10 pups (5 male and 5 female) were sacrificed at 4-h intervals during the 24-h period following dosing. Adrenals, blood, brain, heart, lung, liver, and kidneys were analyzed for radioactivity. Urine samples were analyzed for radioactivity and metabolites of lindane. There was a significant age-dependent increase in the metabolism of lindane in the rat. High levels of radioactivity in the lung and increased reductive dechlorination suggest that the lung may play a greater role in metabolism of lindane by young rats. Oxidative phase I reactions increased significantly, while anaerobic reductive dechlorination of lindane to 4-chlorophenylmercapturic acid decreased significantly with age. Phase II sulfate and glutathione conjugations decreased significantly and glucuronide conjugation increased significantly with age. Metabolism and excretion of lindane appear to parallel development of the hepatic enzymes involved in phase I and phase II reactions.

Aging↗
PubMed1985

Comparison of in vivo and in vitro methods for assessing effects of allyl alcohol on the liver.

Allyl alcohol was administered intraperitoneally (i.p.) to female Fischer 344 rats at doses of 0, 3, 10 and 30 mg/kg daily for 7 days. Plasma sorbitol dehydrogenase was minimally elevated. No dose-related changes were observed in hexobarbital oxidation, aniline hydroxylation, or ethylmorphine demethylation. Aldrin epoxidation was slightly elevated. Naphthol glucuronidation and glutathione-S-transferase activity with 1,2-dichloro-4-nitrobenzene were increased. Results from in vivo studies on the metabolism of lindane were in close agreement with the in vitro measurements suggesting that daily treatment for one week with allyl alcohol at doses of 3, 10 and 30 mg/kg has no significant effect on phase I pathways, has a selective effect on phase II pathways and, under the conditions of this experiment, has minimal hepatotoxic effects in these rats.

1-Propanol↗
PubMed1985

Comparison of in vitro methods and the in vivo metabolism of lindane for assessing the effects of repeated administration of ethanol on hepatic drug metabolism.

In vitro methods of assessing alterations in drug metabolism and the measurement of lindane metabolites in urine were compared for their ability to determine the influence of ethanol on drug metabolism. Ethanol was administered intraperitoneally (i.p.) to young adult female rats daily for 7 days at doses of 0.12, 0.60 and 3.0 ml/kg. No alterations were observed in ethylmorphine demethylation, hexobarbital oxidation or glucuronyltransferase. Aniline hydroxylation was decreased at the high dose level and aldrin epoxidation was increased at the intermediate dose. In vivo only the high dose of ethanol produced significant changes with significant increases observed for the oxidation of lindane to alcohol metabolites, the glucuronidation of the alcohol but not the chlorophenol metabolites, and glutathione conjugation. The latter increase was also observed in vitro. The in vivo and in vitro data suggest a minimal effect of ethanol on drug metabolism at low levels of administration.

Animals↗
PubMed1985

Comparison of in vivo and in vitro methods for assessing the effects of phenobarbital on the hepatic drug-metabolizing enzyme system.

The effect of daily i.p. injections of 0, 1, 10 and 80 mg/kg phenobarbital for 1 week on the activity of the hepatic drug-metabolizing enzyme system was measured in the rat by a model substrate assay employing lindane (gamma-HCH) and by a battery of in vitro enzyme assays. Comparison of the dose-response curves of the in vivo and in vitro assays indicated that urinary metabolites of lindane provided a good index of phenobarbital-induced change in both phase I and phase II reactions.

Animals↗
PubMed1985

Effects of age and obesity on the metabolism of lindane by black a/a, yellow Avy/a, and pseudoagouti Avy/a phenotypes of (YS x VY) F1 hybrid mice.

Lindane (gamma-hexachlorocyclohexane) has been shown to produce hepatomas in some strains of mice but not in others. Genetic factors and/or altered metabolism may play a role in the susceptibility to lindane-induced hepatomas. This study reports the effect of age and obesity on the comparative metabolism and disposition of lindane in obese yellow Avy/a and in lean pseudoagouti Avy/a and black a/a phenotypes of (YS x VY) F1 hybrid female mice at 8, 17, 30, 56, and 86 wk of age. At 24 h prior to sacrifice the mice were dosed p.o. with 18 mg lindane (containing 55 microCi [U-14C]lindane/kg). Aging altered the biotransformation of lindane such that while the excretion of lindane and its metabolites declined, the proportion of conjugated and polar metabolites increased. Tissue storage was elevated in older animals. In the yellow Avy/a mice, which are known to have a predisposition to the formation of hepatomas, there was accelerated and prolonged growth, reduced metabolite excretion, a greater proportion of conjugated metabolites, and higher dechlorinase activity compared to that of their pseudoagouti Avy/a and black a/a siblings.

Age Factors↗
PubMed1975

Ascorbic acid requirements and metabolism in relation to organochlorine pesticides.

Those organochlorine pesticides which possess both high lipoid solubility and high resistance to biodegradation are prone to accumulation in animal tissues and produce relatively long-term effects as toxicants. Such compounds, typified by DDT, Dieldrin, and Lindane, are profound inducers of hepatic microsomal enzymes, including parts of the glucuronic acid and ascorbic acid biosynthetic pathways. Consequently, administering such pesticides to rats in accompanied by enhanced formation and excretion of D-glucuronic acid and L-ascorbic acid, or D-glucaric acid in the case of guinea pigs. Secondarily, the efficiency in biodegrading the pesticides is reduced in ascorbic-acid-deficient guinea pigs with correspondingly greater residue accumulation in tissue. This would aggravate chronic toxic effects of the compounds. Finally, the capacity of the liver to adapt to the presence of such toxicants through enhanced microsomal enzymatic levels appears to be sensitive to its ascorbate status. Impaired enzyme induction is apparent quite early during ascorbic acid depletion in guinea pigs. The enhanced turnover of ascorbate produced by such pesticides, the poor enzymatic adaptation to them during ascorbate depletion and the dependency of the oxidase system upon adequate ascorbate, all point to the central significance of ascorbate status in the liver, and possibly other tissues, as a determinant of their chronic toxicity.

Animals↗
PubMedDate not supplied

A comparison of in vitro and in vivo methods for evaluating alterations in hepatic drug metabolism following mercuric chloride administration.

Mercuric chloride was administered once i.p. to female Fischer-344 rats at doses of 0, 0.2, 0.6 and 1.8 mg/kg. Although there were no alterations in the urinary excretion of lactate dehydrogenase, significant elevations in the activities of urinary (U) alkaline phosphatase, glutamic-pyruvic transaminase (GPT) and glutamic-oxalacetic transaminase (GOT) indicated that mercuric chloride was nephrotoxic. There was no evidence of hepatotoxicity as hepatic glucose-6-phosphatase and serum sorbitol dehydrogenase were essentially unaffected by mercuric chloride administration. The activities of ethylmorphine demethylase, hexobarbital oxidase and aldrin epoxidase determined in vitro were not inhibited by mercuric chloride although aniline hydroxylase activity was decreased. Of the four phase-II reactions measured, only the glucuronidation of chloramphenicol was diminished by treatment with mercuric chloride. Results from the in vivo studies on the metabolism of lindane, which indicated no change in the excretion of free or conjugated metabolites, were in close agreement with the in vitro data suggesting that the nephrotoxic effects of mercuric chloride do not alter the urinary excretion of the model substrate lindane.

Animals↗