Susceptibility to phenobarbital promotion of hepatotumorigenesis: correlation with differential expression and induction of hepatic drug metabolizing enzymes in heavy and light male (C3H x VY) F1 hybrid mice.

Higher body and carcass (body - liver) weights in sodium phenobarbital (PB) treated mice correlate with formation of multiple hepatocellular adenomas in yellow Avy/A and agouti A/a (C3H x VY) F1 hybrid male mice. To assess differences in PB induction of hepatic drug metabolizing enzymes, yellow Avy/A (C3H x VY) F1 hybrid male mice were fed 0.05% sodium PB in NIH-31 diet for 7 months. Livers from the heaviest and lightest mice in the untreated and PB groups were assayed. Total cytochrome P450 content, cytochrome P450IA-selective 7-ethoxyresorufin-O-deethylase and P450IIIA-selective testosterone-6 beta-hydroxylase activities were preferentially induced in the light mice. In contrast, P450IIB-selective 7-pentoxyresorufin-O-dealkylase activity was increased only 3-fold by PB in the light mice but 6-fold in the heavy mice. Testosterone UDP-glucuronyltransferase and gamma-glutamyltranspeptidase activities were induced in the light mice but not in the heavy mice. Glutathione-S-transferase N1:1-dependent activity was induced preferentially in the heavy mice. Significant differences also occurred in constitutive expression of P450IIIA-selective testosterone-6 beta-hydroxylase, P450IA-selective 7-ethoxyresorufin-O-deethylase and testosterone UDP-glucuronyltransferase activities between the untreated weight groups. Thus, expression of constitutive and PB-inducible forms of hepatic drug metabolizing enzymes differs between heavy and light Avy/A (C3H x VY) F1 hybrid subpopulations. This suggests that differential susceptibility to PB promotion of hepatocellular adenomas among genetically identical mice is accompanied by differences in the regulation of gene expression.

Pharmacokinetics of 2,4,5-T in mice as a function of dose and gestational status.

A pharmacokinetic study was conducted in CD-1 mice with the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) as a function of dose (15, 30, 60, and 90 mg/kg, iv) and gestational status (nonpregnant, day 6, 10, 13, and 17 of gestation, and postpartum). Analysis for 2,4,5-T and its metabolites was based on an electron-capture gas-liquid chromatographic method. Pharmacokinetic stimulation of the blood, urine, and feces data from each mouse was performed on an analog-digital hybrid computer system based on a two-compartment model with parallel, first-order elimination kinetics. Data analysis demonstrated dose-independent kinetics for most pharmacokinetic parameters but a gestational status-dependence. There was a tendency, as indicated by an increase in the biologic half-life and AUC and decrease in clearance and total percent recovery, for pregnant animals to eliminate 2,4,5-T more slowly as gestation progressed, resulting in potentially increasing fetal exposure during the later stages of pregnancy.

The in vitro embryotoxicity of 5-fluorouracil in rat embryos.

The fluorinated pyrimidine 5-fluorouracil (5-FU) is an effective chemotherapeutic agent that is teratogenic in a number of species. The mechanism for the embryopathic effect of the drug is unknown. We examined the effects of this compound on gestation day 10.5 rat embryos cultured for 48 hours in a rodent whole embryo culture system. Embryos were exposed for 1-4 hours to various doses of 5-FU. Embryolethality was minimal in all treatment groups. The malformation frequency increased with higher doses; within a dose, the malformation frequency increased with longer exposure to the drug. The tail and hindlimb bud were the most commonly affected structures in vitro; tail and leg defects are produced in several species by exposure to the drug in vivo. The embryopathic drug concentration in the culture media (2-8 micrograms/ml) is similar to the plasma level of 2-17 micrograms/ml, which is associated with embryopathy in vivo. Results from this study suggest that the whole embryo culture system is an appropriate model for developmental toxicity studies of 5-FU.

Comparative stability of physiological parameters during sustained anesthesia in rats.

Rats were anesthetized with pentobarbital, pentobarbital and atropine, inactin [5-ethyl-5-(1'-methyl-propyl)-2-thiobarbiturate], ether and inactin, or urethane. Cardiovascular and arterial acid-base parameters were monitored over a 3-hour period of anesthesia. Heart rate, arterial pressures, and pH progressively decreased with duration of pentobarbital anesthesia. Changes observed in rats anesthetized with the thiobarbiturate, inactin, were similar although generally less severe. Most subjects treated with the barbiturates were markedly hypercapnic. Urethane anesthesia was characterized by a higher and more stable heart rate and greater pulse pressure. Arterial carbon dioxide and bicarbonate levels in the urethane group were substantially lower at all sampling times than the values obtained in the barbiturate groups.