ABSTRACT
Interferon alfa-2a (Roferon-A, Hoffmann-La Roche Inc., Nutley, NJ) is identical to one of approximately 15 subtypes of interferon alpha made by human leukocytes and is produced in bacteria using recombinant DNA techniques. In its antiviral, antiproliferative, and immunomodulatory activities it is similar to leukocyte interferon alpha. These activities are species-restricted and have been demonstrable, thus far, only in humans, certain other primates, bovines, and guinea pigs or cells derived therefrom. The possibility that the toxicity of interferon alfa-2a would also be species-restricted appears to have been confirmed by results obtained thus far. Toxicological studies in rats, mice and several species of monkeys have failed to indicate the side effects that have been observed in humans. However, studies in species in which interferon alfa-2a is active and in others in which it is not, have revealed similar pharmacokinetics and elimination mechanisms.
Subject(s)
Interferon Type I/therapeutic use , Neoplasms, Experimental/drug therapy , Recombinant Proteins/therapeutic use , Virus Diseases/drug therapy , Animals , Antibody Formation , Cattle , Cell Line , Cells, Cultured , Cricetinae , Drug Evaluation, Preclinical , Haplorhini , Humans , Interferon Type I/metabolism , Metabolic Clearance Rate , Mice , Mice, Nude , Neoplastic Stem Cells/pathology , Rabbits , Rats , Recombinant Proteins/metabolism , Species SpecificityABSTRACT
This paper is a review of the acute, subchronic, and chronic toxicity, mutagenicity, carcinogenicity, and teratogenicity of vitamin A, tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), and etretinate. The results of in vitro mutagenicity testing of the retinoids are also presented. In addition to teratogenesis studies, experiments designed to evaluate the effects of the retinoids on fertility and reproductive performance and on perinatal and postnatal development are also described.
Subject(s)
Abnormalities, Drug-Induced/etiology , Neoplasms/chemically induced , Vitamin A/analogs & derivatives , Animals , Dogs , Female , Mice , Mutagenicity Tests , Pregnancy , Rats , Reproduction/drug effects , Vitamin A/adverse effects , Vitamin A/toxicitySubject(s)
Chemical and Drug Induced Liver Injury/prevention & control , Dimethylnitrosamine/antagonists & inhibitors , Nitrosamines/antagonists & inhibitors , Pharmaceutical Preparations/metabolism , Vitamin E/pharmacology , Animals , Cytochromes/metabolism , Dimethylnitrosamine/blood , Dimethylnitrosamine/toxicity , Heme/metabolism , Male , Methyltransferases/metabolism , Microsomes, Liver/enzymology , Mixed Function Oxygenases/metabolism , RatsSubject(s)
5-Aminolevulinate Synthetase/antagonists & inhibitors , Aminobutyrates/pharmacology , Anti-Bacterial Agents/pharmacology , Porphobilinogen Synthase/antagonists & inhibitors , Aminolevulinic Acid/urine , Animals , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Male , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Porphobilinogen/urine , Porphyrins/metabolism , RatsABSTRACT
The major metabolic pathway of the (-) enantiomer and the (+) enantiomer of 2-hydroxy-N-cyclopropylmethylmorphinan in dogs was shown to be conjugation with glucuronic acid and/or sulfate. Gas chromatography mass spectrometry, nuclear magnetic resonance spectroscopy and X-ray crystallography were used to identify additional metabolites of the two enantiomers in dog urine after hydrolysis with Glusulase. Metabolites of the (-) enantiomer were identified as 2-hydroxymorphinan and 2,7beta-dihydroxy-N-cyclopropropylmethylmorphinan. The major metabolites of the (+) enantiomer in hydrolyzed dog urine were identified as 2-hydroxymorphinan,2,3-dihydroxy-N-cyclopropylmethylmorphinan and 2-methoxy-3-hydroxy-N-cyclopropylmethylmorphinan. In addition, tentative or partial structures were postulated for three minor metabolites of the (+) enantiomer: 2-methoxy-3-hydroxymorphinan, a metabolite containing a hydroxyl group on either carbon 4, 5, 6 or 7 and a methylated catechol metabolite containing a hydroxyl group on carbon 4, 5, 6 or 7. Thus, the major oxidative pathways of the (-) enantiomer were N-dealkylation and aliphatic hydroxylation, while the (+) enantiomer mainly underwent N-dealkylation and aromatic hydroxylation, followed by phenolic methylation. Analysis of urine from a human subject administered the (-) enantiomer suggested that the metabolism of this isomer by man was similar to its metabolism by dog.
Subject(s)
Morphinans/metabolism , Analgesics/metabolism , Animals , Chromatography, Gas , Cyclopropanes/metabolism , Dogs , Humans , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Models, Molecular , Narcotic Antagonists/metabolism , Stereoisomerism , X-Ray DiffractionABSTRACT
alpha-Tocopherol has been evaluated as a nitrite scavenger for the prevention of nitrosamine formation in a model system and under practical conditions. alpha-Tocopherol was found to react with nitrosating agents in both lipophilic and aqueous environments. The use of alpha-tocopherol was shown to inhibit aminopyrene-nitrite induced hepatotoxicity in rats and to reduce the amount of NDMA formed in cigarette smoke. Of primary interest is the finding of a significant reduction of NPYR formation in fried bacon. Nitrosamine inhibition was greater with alpha-tocopherol used in combination with sodium ascorbate than with sodium ascorbate alone.
Subject(s)
Nitrosamines/metabolism , Vitamin E/pharmacology , Animals , Ascorbic Acid , Chemical Phenomena , Chemistry , Hydrogen-Ion Concentration , Meat/analysis , Nitrites , Nitrosamines/analysis , Rats , Smoking/metabolism , SwineSubject(s)
Ascorbic Acid Deficiency/metabolism , Microsomes/metabolism , Pharmaceutical Preparations/metabolism , Animals , Carcinogens/metabolism , Coumarins/metabolism , Enzyme Induction/drug effects , Guinea Pigs , In Vitro Techniques , Intestinal Mucosa/metabolism , Lung/metabolism , Male , Microsomes, Liver/metabolism , Phenobarbital/pharmacologySubject(s)
Aminopyrine/poisoning , Ascorbic Acid/pharmacology , Nitrites/poisoning , Nitrosamines/poisoning , Alanine Transaminase/blood , Animals , Ascorbic Acid/therapeutic use , Chemical and Drug Induced Liver Injury/prevention & control , Dimethylnitrosamine/metabolism , Liver/drug effects , Liver Diseases/prevention & control , Necrosis , RatsSubject(s)
Liver/metabolism , Pharmaceutical Preparations/metabolism , Phenobarbital/pharmacology , Aging , Aniline Compounds/metabolism , Animals , Animals, Newborn , Benzopyrenes/metabolism , Cytochrome P-450 Enzyme System/metabolism , Cytochrome Reductases/metabolism , Dealkylation , Female , Fetus , Gestational Age , Guinea Pigs , Hydroxylation , Liver/drug effects , Liver/ultrastructure , Male , Microscopy, Electron , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Mixed Function Oxygenases/metabolism , Oxidoreductases, N-Demethylating/metabolism , Piperazines/metabolism , Postpartum Period , PregnancySubject(s)
Ascorbic Acid/therapeutic use , Scurvy/drug therapy , Sulfuric Acids/therapeutic use , Administration, Oral , Animal Nutritional Physiological Phenomena , Animals , Ascorbic Acid/administration & dosage , Ascorbic Acid/metabolism , Body Weight , Guinea Pigs , Hemorrhage/prevention & control , Hindlimb , Injections, Intraperitoneal , Joints , Liver/metabolism , Male , Ribs , Scurvy/prevention & control , Structure-Activity Relationship , Sulfuric Acids/administration & dosageSubject(s)
Histamine H1 Antagonists/metabolism , Microsomes, Liver/metabolism , Piperazines/metabolism , Anaerobiosis , Animals , Butanes/metabolism , Carbon Tetrachloride/pharmacology , Cytoplasm , Decarboxylation , Histamine H1 Antagonists/antagonists & inhibitors , Hydroxylation , In Vitro Techniques , Kinetics , Male , Microsomes, Liver/enzymology , NAD , NADP , Oxidation-Reduction , Oxides/pharmacology , Oxygen , Phenobarbital/pharmacology , Piperazines/antagonists & inhibitors , Rats , Subcellular Fractions/metabolismABSTRACT
The oral treatment of rats with sodium ascorbate in combination with sodium nitrite and aminopyrine prevents the rise in serum alanine aminotransferase (EC 2.6.1.2) observed when nitrite and aminopyrine are given alone. Ascorbic acid also affords protection, whereas dehydroascorbic acid exerts no protective effect.
