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Biomedical subjects

G J Dutton

Publications and source records attributed to G J Dutton.

At least 37 records · Page 2Linked to original sources
PubMed1976

Precocious development of UDP-glucuronyltransferase activity in cultured fetal rat liver brought about by glucocorticoids and requiring amino acid incorporation into protein.

Fetal-rat liver explants cultured in a defined protein-free medium containing dexamethasone, corticosterone or cortisol (all 2 microM) exhibit precocious development of UDPglucuronyltransferase activity to o-aminophenol. Transferase activity in 14-day fetal livers cultured with the glucocorticoids for 3 days rises from virtually zero to 5 times the activity seen in fresh 17 day fetal liver. With 15-day fetal livers, precocity was also observed, but to a lesser degree. Precocity always required addition of glucocorticoids, though explants were viable without them. Protein synthesis, not activation, was probably involved, for assays were performed in a range of digitonin concentrations to ensure 'optimal' activation; also, precocious development of transferase activity and uptake of [14C]-leucine into protein exhibited parallel behaviour during inhibition by, and recovery from, cycloheximide-pulsing. This is the first demonstration of a protein-synthesis-dependent stimulation of fetal mammalian UDPglucuronyltransferase by known compounds of endogenous origin. Results with other substrates are discussed.

Amino Acids↗
PubMed1976

Precocious development of UDP-glucuronyltransferase activity in chick-embryo liver after administration of adrenocorticotropic hormone and of certain 11beta-hydroxy corticosteroids.

1. Precocious development of UDP-glucuronyltransferase (EC 2.4.1.17) and of glucuronidation by endogenous compounds of known chemical composition is reported for the first time. 2. This development occurs precociously in chick-embryo liver after administration to the egg of mammalian adrenocorticotropic hormone, of Synacthen (a synthetic compound possessing adrenocorticotropic activity), or of certain corticosteroids possessing a hydroxy or an oxo group at C-11. 3. Corticosterone-dependent transferase development parallels the rise of infused corticosterone in plasma, but does not require the presence of embryo pituitary in ovo, and is demonstrable in embryo liver explants in vitro. 4. Competence of embryo liver transferase to respond to corticosterone (or dexamethasone) begins over days 13-14, the time of competence to respond to grafted pituitary gland. 5. The transferase appearing after treatment with corticosterone or adrenocorticotropic hormone, like that appearing after pituitary grafting or on natural development and unlike that from the untreated embryo, is markedly activated by membrane-perturbation procedures, suggesting it appears through induction, not activation. 6. Thyroxine and tri-iodothyronine accelerate transferase development after treatment with adrenocorticotropic hormone or corticosteroid to the rate seen after pituitary grafting. 7. A wide range of other hormones and steroids did not obviously influence transferase development in this system. 8. We suggest that grafted pituitary gland evokes precocious transferase development in embryo liver through production of adrenocorticotropic hormone and hence of the active corticosteroids; thyrotropin and thyroxine hasten the process. The role of this mechanism in the natural development of UDP-glucuronyltransferase is discussed.

11-Hydroxycorticosteroids↗
PubMed1975

Induction of UDPglucose dehydrogenase during development, organ culture, and exposure to phenobarbital. Its relation to levels of UDPglucuronic acid and overall glucuronidation in chicken and mouse.

Liver UDPglucose in early chick-enbryo has, by the 19th day of incubation, reached levels existing in young hatched (White Leghorn) chicks. In developing ASH/TO mouse liver, the dehydrogenase is low, but increases sharply at late foetal and weaning stages; adult activity is greater in females than males. The UDPglucuronic acid content of embryo liver from at least 12 days resembles that of adult chicken; in mouse liver it rises over birth and infancy. These differences in relative rates of development of enzyme and nucleotide in the 2 species can explain why overall glucuronidation by liver appears in chick rapidly after hatching, but in mouse only gradually during infancy. UDPglucose dehydrogenase increases in embryo liver, probably by induction, 2-3-fold during culture with phenobarbital and some 5-fold when exposed to the drug in ovo. Phenobarbital treatment also increases the enzyme in late foetal and adult mice, abolishing the sex difference. Differences between induction of UDPglucose dehydrogenase and UDPglucuronyl transferase during development, culture and phenobarbital treatment indicate that control mechanism for these two enzymes are not directly linked.

Alcohol Oxidoreductases↗
PubMed1975

Precocious development of glucuronidating and hydroxylating enzymes in chick embryos treated with pituitary grafts.

1. Initiation of precocious development of UDP-glucuronyltransferase by an endogenous factor is reported for the first time. 2. This development occurs in chick embryo liver and kidney after grafting of the cephalic lobe of chicken pars-distalis pituitary tissue on to the chorioallantoic membrane, and in liver results in a rise in the enzyme activity from virtually zero to ;adult' values. Aniline hydroxylase also precociously develops in the liver of grafted embryos, its activity rising from one-third to the full adult value. Specific activities of glucose 6-phosphatase, cytochrome P-450 and NADPH-cytochrome c reductase did not significantly change. 3. The response of the transferase does not require the presence of host pituitary gland nor, apart from 1 day's necessary initiation, the presence of the graft itself. 4. The host becomes competent to respond on the 14th day of incubation; response continues for at least 3 days after removal of the graft, and for 2 days in the isolated liver. Grafting of embryonic pars distalis younger than 17 days does not evoke a response in the host liver. 5. Secretion of the pituitary factor increases suddenly some 24-48h before the naturally developing surge in liver UDP-glucuronyltransferase activity and may be responsible for initiating this rise in vivo. 6. The factor is probably not a growth or luteinizing hormone; its nature and the likelihood of a secondary hormone acting directly on the liver are discussed.

Adrenal Glands↗
PubMed1975

Delayed induction by phenobarbital of udp-glucuronyltransferase activity towards bilirubin in fetal liver.

Phenobarbital pretreatment of pregnant mice (ASH/TO strain) gave rise to approximately equal concentrations of phenobarbital in both maternal and fetal liver. This pretreatment resulted in increased UDP-glucuronyltransferase (GT) activity towards bilirubin in maternal and neonatal liver in fetal liver on days 19 and 20 but in livers from earlier (15-18 day) fetuses GT either was not significantly increased or remained undetectable. Fetal liver is thus not competent to respond to phenobarbital by increasing its GT activity, until just before birth. This pattern persisted through changes in assay conditions and is contrasted with that occuring in embryos free from maternal influence. GT from adult and neontal liver is activated by 0.2 per cent digitonin; in fetal liver this response also does not appear until day 19.

Animals↗
PubMed1975

Relationship beteen activation of "detoxicating" enzymes in stored broken-cell preparations and in autolysing liver.

Activity of UDP-glucuronyltransferase (GT) towards o-aminophenol, p-nitrophenol and bilirubin has been followed in portions of mouse liver stored for periods up to 24 h and in mouse-liver homogenates stored under similar conditions of time and temperature. In both preparations and for all three substrates the pattern of change of GT activity was closely similar. Activity decreased initially, then rose to an optimum higher than in fresh tissue before finally falling. Overall glucuronidation, as measured in slices, also follwed this pattern. The effect of cycloheximide and of detergents, and the levels of UDP-glucose dehydrogenase, UDP-glucuronic acid and aniline hydroxylase were also studied. It is concluded that autolysing liver tissue passes through a period of increased GT activity and glucuronidation corresponding in onset with spontaneous activation of GT in stored homogenates and probably originating by a similiar mechanism. This increase contrasts with progressive fall in hydroxylating activity. The latency of GT in vivo and the value of its activation in damaged liver are discussed.

Aniline Hydroxylase↗