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Biomedical subjects

G W Lucier

Publications and source records attributed to G W Lucier.

At least 145 records · Page 8Linked to original sources
PubMed1979

Developmental toxicology of the halogenated aromatics: effects on enzyme development.

Our studies were designed to define structure-activity relationships for the effects of pure PCB congeners and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hepatic enzyme development. The organohalogens were usually administered to pregnant rats and enzyme activities measured in fetuses and offspring (6, 20, and 55 days after birth). Offspring of pregnant rats exposed to TCDD had elevated levels of benzpyrene hydroxylase and nonsteroid UDP glucuronyltransferase (UDPGT). Postnatal inductive actions of TCDD were caused primarily by newborn exposure to TCDD in milk. 3,4-3',4'-Tetrachlorobiphenyl (4-CB) induced P448-dependent enzymes in 6- and 20 day-old rats whereas 2,4,5-2',4',5'-hexachlorobiphenyl (6-CB) induced P450-dependent enzymes. 4-CB was a potent teratogen (behavioral and kidney abnormalities) but 6-CB produced no such developmental defects. 4-CB might also alter the normal imprinting of sexual differentiation of hepatic metabolism as evidenced by a feminization (decrease) of UDPGT in adult male rats which were exposed neonatally to 4-CB. Therefore, the organohalogens might alter the ontogeny of hepatic metabolism in two ways: induction and imprinting.

Animals↗
PubMed1979

Altered sexual differentiation of hepatic uridine diphosphate glucuronyltransferase by neonatal hormone treatment in rats.

The hepatic microsomal enzyme UDP-glucuronyltransferase undergoes a complex developmental pattern in which enzyme activity is first detectable on the 18th day of gestation in rats. Prepubertal activities are similar for males and females. However, postpubertal sexual differentiation of enzyme activity occurs in which male activities are twice those of females. Neonatal administration of testosterone propionate or diethylstilboestrol to intact animals resulted in lowered UDP-glucuronyltransferase activity in liver microsomal fractions of adult male rats, whereas no changes were observed in the adult females and prepubertal male and female animals. Neonatal administration of testosterone propionate and diethylstilboestrol adversely affected male reproductive-tract development as evidenced by decreased weights of testes, seminal vesicles and ventral prostate. Diethylstilboestrol also markedly decreased spermatogenesis. Hypophysectomy of adult male rats resulted in negative modulation of microsomal UDP-glucuronyltransferase and prevented the sexual differentiation of enzyme activity. In contrast hypophysectomy had no effect on female UDP-glucuronyltransferase activity. A pituitary transplant under the kidney capsule was not capable of reversing the enzyme effects of hypophysectomy, therefore suggesting that the male pituitary factor(s) responsible for positive modulation of UDP-glucuronyltransferase might be under hypothalamic control in the form of a releasing factor. Neonatal testosterone propionate and diethylstilboestrol administration apparently interfered with the normal sequence of postpubertal UDP-glucuronyltransferase sexual differentiation.

Age Factors↗
PubMed1979

Metabolic activation/deactivation reactions during perinatal development.

The role of metabolic activation/deactivation reactions during development is evaluated in relation to developmental pharmacology and toxicology. Enzyme systems evaluated include the mixed-function oxidases (aryl hydrocarbon hydroxylase and oxidative demethylation), epoxide hydration and conjugation (glutathione conjugation, sulfation, and glucuronidation). Placental transfer and milk secretion of chemicals are discussed in relation to maternal, placental, and fetal metabolism. Normal patterns of enzyme development can be modified in two ways: (1) enzyme induction and (2) enzyme imprinting. Postnatal induction of the mixed-function oxidases and glucuronyl-transferase following treatment of pregnant rats with TCDD is shown to be caused primarily by newborn exposure to TCDD in milk. Structure-activity relationship are defined for the perinatal induction of hepatic enzymes by the pure PCBs. PCBs are divided into two classes: P-450 inducers and P-448 inducers. Imprinting or programming of hepatic metabolism is a function of the sexual differentiation of enzyme activity; male and female activities are similar in prepubertal animals, whereas pronounced sex differences are evident in adults. Treatment of newborn rats (days 2--6) with diethystilbestrol or testosterone resulted in a feminization (decrease) of mixed-function oxidation and glucuronidation in adult males. No changes were seen in immature males or females or adult females. This effect appears to be irreversible and is under pituitary-hypothalamic-gonadal control. In addition to the feminization of enzyme activity, neonatal exposure to hormonally active chemicals also feminizes the hepatic response to cadmium in resultant adult animals.

Animals↗
PubMed1978

The differential response of isolated intestinal crypt and tip cells to the inductive actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The cell specific induction of uridine diphosphate(UDP)-glucuronyltransferase by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in intestinal epithelium was studied by administering [14C] TCDD (8 microgram/kg to adult female rats). Intact epithelial cells from the tip and crypt regions were isolated by differential vibration of rat duodenum. Cell separation was monitored by electron microscopy and marker enzymes. UDP-glucuronyltransferase and radioactivity were assayed in both cell types 0 h, 3 h, 10 h, 1 day, 3 days and 5 days after treatment. UDP-glucuronyltransferase activities were not significantly changed in either cell type isolated from TCDD-treated rats until 24 hr after treatment when a three-fold increase in crypt cell activity was evident. No significant changes in UDP-glucuronyltransferase activity were observed in the differentiated tip cells until 3 days after TCDD treatment. UDP-glucuronyltransferase was increased approximately two-fold in both cell types from 3 and 5 days following TCDD treatment. There was a negative correlation between the time-course of UDP-glucuronyltransferase induction and the [14C]TCDD concentrations measured in these cells. These studies suggest that the undifferentiated cells of the intestinal crypt region are more sensitive to TCDD inductive actions than are the absorptive tip cells.

Animals↗
PubMed1977

Tetrachlorodibenzo-p-dioxin induction of renal microsomal enzyme systems: ultrastructural effects on pars recta (S3) proximal tubule cells on the rat kidney.

A single oral administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin to rats at a dose level of 25 microgram/kg produced marked proliferation of smooth endoplasmic reticulum in renal proximal tubule cells of the straight (S3) segments. This ultrastructural effect was associated with a pronounced induction of the microsomal enzymes glucuronyl transferase and benzopyrene hydroxylase which persisted for at least 16 days after treatment. Renal dissection studies disclosed that the activities of these enzymes in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated animals were not uniformly distributed within the kidney but followed the general known distribution of S3 cells. Enzyme activities were highest in the outer stripe of the medulla and cortex and lowest in the medulla. These studies demonstrate that the kidney does possess inducible microsomal enzyme systems, capabilities of which have not been appreciated previously due to the lack of a suitable inducing agent and their apparent concentration in a relatively small population of proximal tubule cells.

Animals↗
PubMed1976

Perinatal development of conjugative enzyme systems.

The problems and priorities involved in studying the role of conjugagive enzymes in developmental pharmacology are discussed and evaluated. The relative rates of UDP glucuronyltransferase and beta-glucuronidase were studied during perinatal development in hepatic and extrahepatic tissues to determine the net balance of glucuronidation or deglucuronidation at different developmental stages. In general, deglucuronidation predominated over glucuronidation in fetal tissues whereas the converse was evident in adults. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an extremely toxic contaminant of some organochlorine compounds, was shown to be a potent inducer of some hepatic and extrahepatic drug-metabolizing enzymes. TCDD, administered during gestation, induced the postnatal activities of p-nitrophenol glucuronyltransferase and benzpyrene hydroxylase in rats. Foster mother experiments revealed that the postnatal induction was caused primarily by newborn exposure to TCDD in the mother's milk. Tissue distribution experiments with TCDD-14C confirmed these findings. Although TCDD induced non-steroid glucuronidation, no significant effects were evident on the postnatal development of steroid glucuronidation. The synthetic estrogen diethylstilbestrol (DES) is metabolized primarily by glucuronidation. The postnatal development of DES glucuronidation, like the steroid pathway, was not affected by gestational TCDD treatment. The fetal distribution of DES and DES-glucuronide, at different stages of development, correlated well with the perinatal development of steroid glucuronyltransferase activity.

Animals↗
PubMed1976

The potentiation of barbiturate-induced narcosis by procarbazine.

Procarbazine (MIH), N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (NSC-77213), a clinically effective antineoplastic agent, induced sleep in mice at its optimally effective dose (400 mg/kg) and prolongs hexobarbital sleeping times. MIH (400 mg/kg) increased the period of sleep following hexobarbital (100 mg/kg) nearly 10-fold. Nonhypnotic doses of MIH also significantly prolonged hexobarbital-induced sleep. Hexobarbital half-life in plasma was prolonged 6 to 7 times by prior treatment with MIH (400 mg/kg). Liver microsomes from mice treated with MIH exhibited decreased metabolism of the following substrates in vitro: hexobarbital, aminopyrine, ethylmorphine, and aniline. Cytochrome P-450 levels were also decreased by MIH treatment. Maximal decreases in enzyme activity and P-450 content occurred between 4 and 8 hours following treatment. Pretreatment with phenobarbital decreased the effectiveness of MIH to prolong hexobarbital sleeping times while pretreatment with SKF 525A added to the potentiating effect of MIH. Two major metabolites of MIH had neither central nervous system hypnotic effect nor inhibited hepatic microsomal mixed-function oxidases. Therefore, MIH potentiation of hexobarbital-induces sleep is probably due both to its direct hypnotic effect and inhibition of mixed-function oxidase activity.

Animals↗
PubMed1975

Hepatic and extrahepatic N-acetyltransferase. Perinatal development using a new radioassay.

We report a sensitive and rapid radioassay method for p-aminobenzoic acid N-acetyltransferase. The principle of this assay involves acetylation of p-aminobenzoic acid with [1-14C] labeled acetyl coenzyme A and direct extraction of enzymically formed radioactive p-acetamidobenzoic acid into nonaqueous scintillation fluid. Using this radiometric assay, hepatic and extrahepatic tissue distributions from rat and rabbit were studied. Rabbit blastocyst and endometrial N-acetyltransferase specific activities were equivalent to hepatic activities. Perinatal development studies in rats and rabbits revealed that fetal and neonatal animals are capable of N-acetylation. Rat liver developmental studies exhibited two peaks of activity with the first peak occurring in the late fetus followed by a second peak 3 days after birth. Rabbit fetal and neonatal enzyme activity increased to adult levels by the second week after birth in liver and gut, however, lung showed a different developmental pattern. These studies demonstrate that fetal extrahepatic tissues, like adult tissues, play an important role in N-acetylation.

Acetyltransferases↗
PubMed1975

Postnatal stimulation of hepatic microsomal enzymes following administration of TCDD to pregnant rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) administered to pregnant rats at 3 mu-g/kg as a single oral dose during early, middle, or late gestation caused marked elevations of some maternal hepatic microsomal enzymes for at least 10 weeks after treatment. This dose was not teratogenic and fetal rates of glucuronidation of testosterone and p-nitrophenol (PNP) were unaffected. Increases in fetal liver benzpyrene hydroxylase (BPH) activities were evident during late gestation although cytochrome P-450 and cytochrome b-5 contents were unchanged. The offspring of pregnant rats administered TCDD had markedly elevated hepatic PNP UDP-glucuronyltransferase (UDPGT) BPH, and microsomal cytochrome contents whereas the perinatal development of testosterone UDPGT was unchanged. PNP glucuronidation attained a maximal 8-fold increase above controls by 3 weeks after birth and activities were twice that of controls 8 weeks after birth (adults). Maximal increases in benzpyrene hydroxylation rates occurred one day after birth when in the prenatally exposed group activities were approximately 20 times higher than controls. Foster mother experiments demonstrated that the postnatal inductive effect resulted both from exposure of newborns to TCDD via maternal milk and the activation of an inducing mechanism occurring after birth. Tese data demonstrate that multiple factors are responsible for the induction of hepatic microsomal enzymes in the newborn following administration of TCDD to pregnant rats.

Animals↗