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.
D000818:Animals; D000831:Animals, Newborn; D001711:Biotransformation / Q000187:drug effects; D002273:Carcinogens; D004147:Dioxins / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000201:enzymology; D005865:Gestational Age; D007774:Lactation; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008892:Milk / Q000187:drug effects / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats
D002273:Carcinogens; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins