Robert L. Dixon

Effect of Chloramphenicol on the Metabolism and Lethality of Cyclophosphamide in Rats

Summary Chloramphenicol pretreatment reduced the lethality of cyclophosphamide in vivo and resulted in an increased time of mean death and a higher mean lethal dose. Chloramphenicol pretreatment decreased the in vivo conversion of cyclophosphamide to a metabolite capable of alkylation. After pretreatment with chloramphenicol, a decreased amount of activated product appeared in the urine during 90 min and blood levels of active metabolite were less when measured after 90 min. In vitro chloramphenicol decreased the metabolism of cyclophospamide 50% at approximately 10-3 M. It is concluded that the protection afforded animals by chloramphenicol after treatment with lethal levels of cyclophosphamide is due to an inhibition of microsomal drug-metabolizing enzymes which are responsible for the in vivo activation of cyclophosphamide.

The effects of β-diethylaminoethyl-diphenylpropylacetate (SKF 525-A) on biological membranes—I: SKF 525-A-induced stabilization of human erythrocytes

Abstract β-Diethylaminoethyl-diphenylpropylacetate (SKF 525-A) results in either hemolysis or stabilization of the red cell membrane. These effects are concentration dependent. At higher concentrations of SKF 525-A (10 −3 M), an increase in hemolysis and a decrease in osmotic resistance is noted, whereas a stabilization of the red cell membranes occurs at lower concentrations of 10 −4 –10 −9 M. The hemolysis of the red cell is temperature dependent and hemolysis increases as temperature decreases. The SKF 525-A action appears to be immediate and the effects prolonged. The concentration at which SKF 525-A demonstrates its greatest membrane stabilization corresponded to the first breaking point observed during measurements of surface tension, and thus perhaps indicates the formation of micelles. It can be calculated that one molecule of SKF 525-A occupied 51 A 2 of red cell area. SKF 525-A (10 −4 M) causes a change in the mean cellular volume of red cells over all osmolar concentrations studied. One possible mechanism of action that would account for these findings is that the erythrocyte membrane expands in combination with SKF 525-A in the same way that lipid monolayers interact with various surface-active drugs such as the phenothiazine derivatives. The resulting expansion of the erythrocyte membrane would lead to an increase in the surface area and volume of the red cell and thus decrease osmotic fragility.

Studies of the perinatal differences in the activity of hepatic δ-aminolevulinic acid synthetase☆

Abstract Hepatic δ-aminolevulinic acid (ALA) synthetase activity in prenatal rats, rabbits and guinea pigs is four to eight times the adult level. During the period of elevated activity, ALA synthetase is relatively much less responsive to induction by 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC) or to repression by hemin than is observed in adult rats and rabbits. No induction of ALA synthetase could be demonstrated in fetal rats. In newborn rabbits, hemin caused no significant reduction in ALA synthetase activity, whereas the adult enzyme activity was reduced to 32 per cent of control. This difference in response to hemin was also demonstrated in fetal and newborn rats. Refractoriness to induction decreases as enzyme activity decreases to adult levels. These studies indicate that the neonate may not regulate the activity of hepatic ALA synthetase at the same level as the adult. It is suggested that increasing repression of the enzyme to lower basal levels occurs as the animals mature, bringing the activity and response to DDC and hemin to the levels observed in adults. Perinatal alterations in the regulation of hepatic ALA synthetase activity may account for some of the problems associated with heme metabolism in the newborn and the toxic effects of bilirubin and various drugs.

Perinatal differences in delta-aminolevulinic acid synthetase activity☆

Abstract Prenatal levels of ALA synthetase are higher in rats, rabbits and guinea pigs than in adult animals. The rat and rabbit reach the lower adult levels within the first week of life, while the guinea pig activity declines during the late prenatal period. It is suggested that the regulation of this enzyme in fetal and neonatal animals is less effectively controlled than in adult animals of the same specie. The possible etiology of an increased perinatal ALA synthetase activity and its suggested role in neonatal jaundice, erythropoiesis, and deficiency of microsomal drug metabolizing enzyme systems are discussed.

Neonatal differences in the induction of hepatic aminolevulinic acid synthetase

Abstract The induction of hepatic aminolevulinic acid (ALA) synthetase, an enzyme postulated to be normally regulated by genetic repression, was studied in neonatal and adult rabbits. The basal activity in vitro of ALA synthetase in newborn rabbits is six to eight times that seen in adult animals. Subcutaneous treatment of each age group with the inducing agent, 3,5-dicarbethoxy-l,4-dihydrocollidine (DDC), demonstrated that the neonatal animals were relatively much less responsive to the inducing agent than the adult rabbits. The basal enzyme activity in newborn animals was only doubled while, in contrast, the synthetase activity in adult animals was increased 19-fold. These findings suggest that the regulation of the synthesis of hepatic heme in neonatal animals may be less strictly controlled than in adults. It is suggested that synthesis of ALA synthetase during the neonatal period is semiconstitutive.

Selective postnatal development of Na,K-activated-adenosinetriphosphatase in rabbit kidneys.

Summary Renal ATPase activity was measured in rabbits of different ages. Total Na,K-activated; Mg-dependent-ATPase activity increased gradually with age from newborn to adult. Mg-dependent-ATPase, however, remained essentially unchanged and equivalent to the adult level during development. Na,K-activated-ATPase was nearly absent at birth and at 5 weeks of age approached levels comparable to those of the adult. The increase in total ATPase activity was due to this selective increase in the Na,K-activated component. The development of Na,K-activated-ATPase activity correlates well with the reported maturation of renal transport mechanisms for amino acids, p-aminohippuric acid, and sodium ion during the perinatal period.

Various factors affecting the lethality of cyclohexylamine

Abstract Cyclohexylamine (CHA) is a metabolite of the artificial sweetening agent cyclamate and has been shown to possess sympathomimetic actions like those of tyramine and/or amphetamine. Acute toxicity studies using male albino Swiss Webster mice indicated that CHA lethality is both temperature and aggregation dependent. Toxic doses of CHA produced behavior characterized by general hyperactivity, resembling the signs following amphetamine treatment. CHA appeared to increase body temperature. The lethality after CHA could be correlated with an increase in body temperature at doses lower than 480 mg/kg only. Drug interaction studies demonstrated that chlorpromazine, reserpine, phenoxybenzamine and tolazoline were each capable of protecting mice against CHA-induced lethality. In contrast, pretreatment of mice with SKF 525-A potentiated CHA lethality. This potentiation suggests that CHA is further metabolized to less toxic metabolites in mice. Metabolic studies with carbon-labeled acetate indicated that CHA-treated mice expired more 14 CO 2 than control animals, suggesting an enhanced metabolic rate. Death following doses of CHA greater than 480 mg/kg were not apparently related to the hyperthermia, but probably involved other mechanisms related to the sympathomimetic action of CHA.