RAPID PERINATAL CHANGES IN LIVER COPPER, IRON, ZINC, AND M~GANESE IN THE DEVELOP- ING GUINEA PIG O. Epstein, S.K.S. Srai, C.D. Bingle, B. Wood* Department of Medicine, Royal Free Hospital and Department of Biochemistry*, Whittington Hospital, London. U.K.

In the perinatal period, anatomical and biochemical changes occur preparing the fetus and neonate for an independent existence. Failure of anatomical adaptation results in congenital diseases such as atrial septal defect and patent ductus arteriosus. Failure of biochemical adaptation might underlie certain inborn errors of metabolism.

The developing guinea pig (gestation = 69 days) was used to investigate developmental changes in liver Cu, Fe, Zn and Mn. Liver weight doubled in the last trimester and then remained static until the 6th post-natal day when accelerated liver growth occurred. In the last trimester, liver Cu levels increased 6-fold, peaking at birth and then falling by 50% in the 4 days after birth to reach adult concentrations by day 30. Liver Fe remained static until the 65th day of gestation and then increased 4-fold, peaking on the first post-natal day then declining to adult levels by the end of the first week of life. Liver Zn increased from the 6Oth day of gestation, peaking on the Ist post-natal day and falling to adult levels within the ist post-natal week. By contrast, liver Mn concentrations were <50% of the adult throughout gestation and only increased after birth to achieve adult concentrations by the 12th post-natal day.

Comparison of the 4 metals suggests that the ontogeny of each metal is under independent control. In the late phase of gestation there is a strong positive metal balance of Cu, Fe and Zn which reverses rapidly in the first days of life. Liver Mn balance remained strongly positive in this early post-natal phase. We suggest that genetic failure of perinatal adapt- ation might result in inborn errors of metabolism such as Wilson's disease and haemochromat- osis.

CHOLESTASIS AND METABOLIC ACIDOSIS INDUCED BY DIETHYL MALEATE IN RABBITS

A. Esteller, R. Jim~nez, C. Arizmendi ~ , J. M. Medina ~ , J. GonzAlez Department of Animal Physiology and *Department of Biochemistry, Faculty of Pharmacy, Salamanca, Spain.

Diethyl maleate is a compound which binds with glutathione by means of a glutathione S- , transferase and is excreted into bile leading to a rapid depletion of hepatic glutathione. In the rabbit, the activity of the enzyme is fairly low and a study was thus carried out to evaluate the possible effects of diethyl maleate on biliary secretion and metabolic status in this species. Male New Zealand rabbits were used. Diethyl maleate was administered intraperitoneally at a single dose of 3.2 umol/kg mixed i/i (v:v) in corn oil. Controls received only corn oil. The administration of diethyl maleate induced a transient choleresis followed by cholestasis. The increase in bile flow reached a maximum at 15-30 min after injection and coursed with significant increases in the biliary output of sodiL~n and u~]accounted anions, whereas that of bile acids was unaffected. Our data seem to confirm that choleresis is due to the osmotic activity of diethyl maleate compounds excreted into bile. Cholestasis was a progressive phenomenon, with bile flow values half those of the controls at two hours after diethyl maleate ac~ninistration, and coursed with significant falls in the output of sodi~n, chloride and bicarbonate, though that of bile acids remained constant. Following diethyl maleate administration, a metabolic acidosis appeared, with progressive increases in blood lactate concentrations. The concentration of this anion in bile closely followed that of pla~na. Cholestasis is attributed to a lowered biliary secretion of bicarbonate, probably secondary to the metabolic alteration. The hepatic values of cytoplasmatic and mitochondrial NAD/NADH ratios and of adenine nucleotide concentrations suggest that the increase in blood lactate resulted rather from a fall in its hepatic utilization than from an increase in its production.

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