UDP-glucuronyltransferase was assayed in liver from adult rhesus monkeys and foetuses during late gestation. Activities toward 2-aminophenol, 5-hydroxytryptamine, l-naphthol and 4-nitrophenol in the foetal liver ranged from 46 to 114% of adult values, whereas activities toward bilirubin, oestradiol and testosterone were less than 5% of adult values. This suggests that in primates UDP-glucuronyltransferase develops differentially in two clusters analogous to that in the rat.

No abstract

Triamcinolone acetonide (TAC) is teratogenic in rats while cortisol has been reported as not teratogenic. The objective of this investigation was to determine whether this difference in teratogenicity could be due to a difference in the metabolism and distribution of the parent compound in the embryomaternal unit. 3H-TAC and 14C-cortisol were administered intramuscularly to pregnant rats on day 12 of gestation. These dams were killed at each of the following time points after injection: 0.5, 1, 3, 6 and 24 hr. Maternal plasma and embryos were analyzed by high performance liquid chromatography (HPLC) and liquid scintillation counting. The plasma concentration of parent TAC was significantly greater than that for parent cortisol at all time points. The plasma elimination half-life for TAC, 86 min, was also calculated to be significantly longer than that for cortisol, 8 min. Furthermore, the percentage of total plasma radioactivity representing HPLC resolved TAC was much higher than that representing cortisol at all time points. The concentration of TAC in the embryos was significantly greater than for cortisol at all time points. The elimination half-life for unchanged TAC in the embryos was 142 min compared to 22 min for cortisol. The percentage of total radioactivity in the embryos representing unchanged TAC was similar to that found in maternal plasma while the percentage of total radioactivity representing unchanged cortisol was much lower than that found in maternal plasma. These findings support the hypothesis that differences in the distribution and metabolism of the parent compound are a critical factor in determining the teratogenicity of that compound.

No abstract

The synthetic glucocorticoid dexamethasone (DEX) and endogenous cortisol were compared in 2 groups of pregnant monkeys of gestational age 143-148 days. In group I, a fetal intraplacental vein and a maternal femoral vessel were catheterized. 3H- Cortisol and 14C-DEX were administered intravenously along with 0.2 mg/kg unlabelled DEX to the mother. Blood and tissue samples were collected to 3 h and urine and feces to 96 h. In group II, 4 of the 7 animals were predosed with DEX 10 mg/kg s.c. for 3 days prior to surgery. The fetus was removed by cesarean section and the in situ placenta was perfused via the umbilical arteries at 15 ml/min X 8 min with 3H-cortisol/14C-DEX in Hanks’ balanced salt solution. Samples were taken from the umbilical vein and uterine vein. In group I, HPLC analysis of paired maternal and fetal plasma samples taken at 10, 20. 60. 120 and 180 min after dosing indicated that the F/M DEX ratio was significantly greater than the F/M cortisol ratio. In fetal lung and liver tissues analyzed, less than 2% of the cortisol remained unmetabolized by 3 h, whereas ≥ 76% DEX remained as parent compound. There was no significant difference between the percentage of DEX (83 ± 7%) and cortisol (73 ± 3%) recovery in maternal urine and feces. In group II, HPLC analysis of paired umbilical vein and uterine vein samples at 2, 4 and 8 min showed that by 8 min 24% of cortisol was converted to cortisone by the uteroplacenta, but only 2.5% of DEX was converted to a metabolite. In DEX-pretreated animals both uterine vein and umbilical vein samples indicated an increase in cortisol to cortisone conversion. A significant increase in DEX metabolism was evident in the uterine vein samples but not the umbilical vein. These data indicate that the fetus is exposed to a higher proportion of DEX than cortisol and that the uteroplacenta plays a larger role in cortisol than in DEX metabolism. In addition, these data suggest that DEX pretreatment enhances the ability of the uteroplacenta to convert cortisol to cortisone.