Herbert S. Posner

Correlation of paraquat toxicity with tissue concentrations and weight loss of the rat.

Abstract Paraquat was administered to Sprague-Dawley and Wistar rats po and iv. Death generally occurred in 2–5 days, but some rats survived for up to 12.5 days. Loss of body weight correlated with lethality, and concentrations in lung and kidney correlated with the degree of toxic response as defined by 2 levels of weight loss and death. The lung became the organ of highest concentration of paraquat through an initial stasis phase, and paraquat was detected in the lungs of all rats that died. The initial half-life of paraquat in plasma and in the tissues was 20–30 min. The subsequent half-life of paraquat in muscle was longest, 4–5 days, and secondary half-lives in the plasma and other tissues were about 2 days. Diquat did not accumulate in lung and muscle as did paraquat, and did not produce the lung pathology. The accumulation in lung (critical organ of pathology), the relatively long secondary half-life of paraquat in the plasma and tissues, the correlation of tissue concentrations with degree of toxic response and the findings with diquat contradict the concept of paraquat as a “hit-and-run” poison.

Induced Synthesis of Liver Microsomal Enzymes Which Metabolize Foreign Compounds

The administration of 3,4-benzpyrene to rats markedly increases the activities of certain liver microsomal enzymes which metabolize foreign compounds. Evidence based on studies of enzyme induction is presented which suggests the presence in liver microsomes of several enzymes which can catalyze the same type of reaction.

Enzymic hydroxylation of aromatic compounds. II. Further studies of the properties of the microsomal hydroxylating system.

Abstract The substrate specificity of the microsomal hydroxylating system has been further investigated. The products of the reactions are phenols in all cases studied, as well as a dihydrodiol in the case of naphthalene, and a dihydrodiol-like compound in the case of quinoline. The conversion of indole to 3-hydroxyindole has been demonstrated. This finding raises the possibiltiy that the indican of the urine might be derived from hydroxylation of indole in the liver rather than from hydroxylation by bacteria in the gut. Evidence is presented for the presence of a family of hydroxylating enzymes in liver microsomes. Although it was not possible to solubilize the hydroxylating enzymes, it was possible to obtain enzymically active microsomal fragments. DPNH was considerably less active than TPNH as a cofactor for the hydroxylation of acetanilide by microsomes from nine animal species. On the contrary, where it was possible to show a stimulation of activity by a reduced pyridine nucleotide, DPNH was more effective than TPNH as a cofactor for the soluble phenylalanine hydroxylase.

Enzymic hydroxylation of aromatic compounds. III. Studies on the mechanism of microsomal hydroxylation.

Abstract The rabbit liver microsomal system has been used to study the mechanism of aromatic hydroxylation. Evidence that dihydrodiols and phenols are not interconvertible is presented. In accord with in vivo findings, benzenoid compounds have been shown to yield only phenols, whereas naphthalene and quinoline have been shown to yield a dihydrodiol and a dihydrodiol-like compound, respectively, as well as phenols. 1,2-Dihydronaphthalene and 1,2-dihydro-1-hydroxynaphthalene (or the 2-hydroxy isomer) do not appear to be intermediates in the conversion of naphthalene to 1,2-dihydronaphthalene-1, 2-diol. Using isotopes to study the conversion of acetanilide to 4-hydroxyacetanilide, it has been shown that molecular oxygen (O 2 ) is utilized in the hydroxylation reaction rather than the oxygen of water. It has also been shown that the hydrogen of tritiated water is not incorporated into the hydroxylated product. No evidence could be found for the utilization of free hydrogen peroxide in the hydroxylation of naphthalene. In accord with the above, several mechanisms proposed for aromatic hydroxylation now appear to be nonoperable, at least in the system under study. It has been proposed that phenols and dihydrodiols are formed from a common intermediate.

Biohazards of methanol in proposed new uses

In the past few years methanol has been proposed for use as an energy source in the place of potentially more scarce natural products. It was also proposed for use as a bacterial feedstock for production of feed protein and the denitrification of waste water. Methanol has a variety of biohazards for the human, most of which have been recognized since the early part of the century. These are discussed in eight categories: hazard at young ages; of potential interactions of several types; abuse; delayed and irreversible toxicity; Inhalation and dermal hazard, as well as that due to oral exposure; toxicity of formaldehyde, its product of incomplete combustion; nearly invisible flame; and a larger storage space requirement than for an equivalent energy yield from gasoline. It is proposed that where a safer compound is available, methanol should not be utilized. However, some of the conditions for reducing the human hazard to methanol are presented. These must be taken seriously and without delay because of the...

On the inability of tryptamine to serve as a precursor of serotonin.

Abstract Tryptamine when administered to animals neither increases the levels of serotonin in tissues nor the amounts of 5-hydroxyindoleacetic acid in the urine. No labeling of tissue serotonin occurred when tryptamine-1-C 14 was administered to rabbits. When rat liver microsomes were incubated with tryptamine, no serotonin could be detected although phenolic material was formed.

Aromatization of hexahydrobenzoic acid by mammalian liver mitochondria

Abstract 1. 1. The enzyme system which aromatizes cyclohexanecarboxylic acid has been shown to be localized in the mitochondrial fraction of guinea pig liver. 2. 2. The sequence of reactions has been shown to be the formation of the CoA derivative of the acid, dehydrogenation and the conjugation with glycine to form hippuric acid. 3. 3. The removal of the oxidation product, benzoic acid, as hippuric acid greatly accelerated the oxidation reaction. 4. 4. Analogy between the present system and the fatty acid oxidase system has been discussed.

Fetal edema from benzhydrylpiperazines as a possible cause of oral-facial malformations in rats☆

Abstract The following findings may help to explain the production of oral-facial malformations, in rats, after the maternal administration of benzhydrylpiperazine compounds: (1) A delay in the process of palate formation occurs when chlorcyclizine is administered, orally, at a dose that yields a 50% incidence of cleft palate (50 mg/kg). (2) At this dose edema, manifested partly as thoracic enlargement, can be demonstrated during the delay. (3) A similar increase in thoracic size, due to the edema, occurs after the administration of four additional benzhydrylpiperazine compounds that produce the oral-facial malformations, when administered at appropriate doses, but not after three other antihistamines that do not yield the cleft palate. (4) Edema formation is dose-dependent at the intermediate doses for cleft palate formation. (5) Finally, edema production is not dependent upon cleft palate production, but cleft palate production may be dependent upon the edema. From these findings and reference to the literature, a mechanism is suggested that relates the production of the cleft palate, micrognathia (receded mandible), microstomia (small mouth), and glossopalatine fusion (fusion of the tongue to the palatine processes) to pressures from fluidenlarged tissue, perhaps partly from the enlarged thorax. The mechanism is discussed.

Placental passage of 14C-dieldrin altered by gestational age and plasma proteins

Abstract As gestation advanced, 14 C-dieldrin concentration increased in the plasma of the maternal rat after a single intravenous dose of the pesticide on Day 13, 16, or 21. The ratio of radioactivity for fetus/maternal plasma decreased only 28 per cent from Day 13 to Days 20 to 21 while the ratios of radioactivity for maternal liver and placenta/maternal plasma decreased more than 65 per cent. With the use of in situ perfusion of the guinea pig placenta, the maternal to fetal transfer of 14 C-dieldrin was shown to change rapidly with type and concentration of protein on the fetal side. Of 5 purified plasma protein fractions perfused on the fetal side, alpha globulins caused the greatest transfer of dieldrin. Fibrinogen, albumin, and the beta globulins were intermediate in effect, and gamma globulins were least effective.

Reduced passage of carbon-14-dieldrin to the fetal rat by phenobarbital but not by eight other drugs or dieldrin

Abstract Pregnant rats were injected intravenously with 14 C-dieldrin on either Day 13, 16, or 21 of gestation. We killed the rats 5 minutes to 24 hours later and assayed fetuses, placentas, and maternal tissues for radioactivity. Radioactivity in the fetus at all three stages of gestation was highest 40 to 60 minutes after the injection. Fetal levels or radioactivity per gram of tissue increased with increasing stage of gestation. Ten drugs and dieldrin itself were screened as potential modifying agents of dieldrin placental transfer. Only phenobarbital pretreatment decreased the amount of dieldrin-related radioactivity in the fetus. The phenobarbital effect was most pronounced 40 minutes and later after dieldrin administration. After the phenobarbital, dieldrin metabolites increased to a greater extent in maternal plasma than in the fetus.