Deuterium Isotope Effect on the Metabolism of the Flame Retardant Tris(2,3-dibromopropyl) Phosphate in the Isolated Perfused Rat Liver

The metabolism of tris(2,3-dibromopropyl) phosphate (Tris-BP)was compared with that of completely deuterated Tris-BP (D15-Tris-BP)in an isolated, recirculating rat liver perfusion system inorder to determine the relative quantitative importance of twodifferent biotransformation pathways of Tris-BP: (i) cytochromeP450-mediated metabolism and (ii) GSH S-transferase-mediatedmetabolism. To accomplish this we quantitated the biliary excretionof S-(3-hydroxypropyl)glutathione (GSOH) as a marker metabolitefor cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl)glutathione (GSOHOH) as a marker metabolite for GSH S-transferase-mediatedmetabolism. Completedeuterium substitution of Tris-BP significantlydecreased the formation of GSOH, whereas there was no effecton the formation of GSOHOH. Because our previous studies showeda large decrease in genotoxicity of D15-Tris-BP compared toTris-BP, the present results support our hypothesis that cytochromeP450-mediated metabolism is responsible for the genotoxic effectsof Tris BP in the rat liver.     

Chronic Marijuana Smoke Exposure in the Rhesus Monkey I. Plasma Cannabinoid and Blood Carboxyhemoglobin Concentrations and Clinical Chemistry Parameters

Chronic Marijuana Smoke Exposure in the Rhesus Monkey I. PlasmaCannabinoid and Blood Carbxyhemoglobin Concentrations and ClinicalChemistry Parameters SLIKKER, W., JR., PAULE, M. G., ALI, S.F., SCALLET, A. C., AND BAILEY, J. R (1991). Fundam. Appl Toxicol17, 321–334. This report is the first in a series abouta large multidisciplinary study designed to determine whetherchronic marijuana (MJ) smoke exposure results in residual behavioraland/or neuropathological alterations in the rhesus monkey. Priorto the initiation of a year of chronic MJ smoke exposure, 64periadolescent male rhesus monkeys were trained for 1 year toperform five operant behavioral tasks and then divided, accordingto their performance in these tasks, into four exposure groups(n=15–16/group): (1) a high dose (HI) group, exposed 7days/week to the smoke of one standard MJ cigarette; (2) a lowd m (LO) group, exposed on weekend days only to the smoke ofa standard MJ cigarate; (3) an extracted MJ cigarette (EX) group,exposed 7 days/week to the smoke of one ethanol-extracted MJcigarette; and (4) a sham group (SH), exposed 7 days/week tosham exposure conditions. Daily exposures for 1 year were accomplishedusing a mask that covered the subjects' nose and mouth. Averagebody weights (initially 3.7?0.5 kg, mean?SD) and rates of weightgain (approximately 0.1 kg/month) were the same for all groupsthroughout the entire experiment. During the first week of expsure,plasma concentrations of -9-tetrahydrocannabinol and 11-nor-9-carboxy-THCin the HI group were 59?7 (mean?SE) and 5.5?1.5 ng/ml, respectively,45 min after MJ smoke administration and did not change significantlyat similar times after exposure throughout the remainder ofthe year. Whole blood carboxyhemoglobin levels increased toapproximately 13% 1 min after expsure to smoke in either theMJ or the EX groups. Comparison of blood chemistry and hematologyvalues before, during, and after exposure indicated no differencesfor most parameters. During exposure, lymphocytes, alkalinephosphatase and -glutamyl transferase were depressed in theHI group compared to in the SH group. During exposure, aspartateaminotransferase was elevatd for both the HI and EX groups,suggesting a general effect of smoke exposure. Because theseeffects were transient and remained within the range of reportednormal values, these data indicate that long-term, experimentalexperimental exposure to MJ smoke is feasible and does not compromisethe general health of the rhesus monkey.     

Immunogenic Properties of Structurally Modified Human Tissue Plasminogen Activators in Chimpanzees and Mice

Immunogenic properties of second generation human tissue plasminogenactivator (tPA) derivatives were examined in chimpanzee andmouse systems. Five species of modified tPAs (mtPAs) (designated2660, 2663, 2810, 8000, and 9200), recombinant native tPA orbovine serum albumin (BSA) as a positive control were subcutaneouslyinjected nine times at suitable intervals into chimpanzees,genetically the closest species to man. These animals were testedfor antigen(Ag)-specific antibodies to the corresponding proteinsby means of enzyme-linked immunosorbent assay and Western blotanalysis. Neither 9200, one of the five mtPAs tested, nor tPAwas immunogenic, although BSA and the other four mtPAs wereimmunogenic under these conditions. Thus, an antigenic determinant was not exposed by the modification on 9200 and thismodified tPA is expected not to be immunogenic in humans. Inthe mouse studies, mice were immunized with mtPAs. Serum sam-piesfrom these animals were tested for antibodies to the mtPAs whichdid not concomitantly recognize native tPA by immune ad sorptionof the antibodies to tPA. The amount of such antibodies alterthe elimination of native tPA-reactive antibodies was littleor none when the serum samples from 9200 and from the othermtPAs, except 8000, were tested. Taking into consideration theresults of the chimpanzee studies, it can be concluded thatAg-specific antibodies are dominantly produced to unchangedepitopes present in modified proteins in the mouse system, inwhich the native protein is immunogenic. These results suggestthat the chimpanzee model should be useful to predict immunogenicityof second generation recombinant proteins in man, while themouse system adopted by us, which determines the newly generatedepitopes of the modified proteins, is not sufficient.     

CONTROL OF BREATHING AFTER FENTANYL AND INNOVAR ANAESTHESIA

Ventilation (VI), end-tidal (Pco₂), mixed venous (PVco₂) andthe ventilatory response to carbon dioxide were measured beforesurgery, and during the first 4h of recovery in 18 adult patientswho underwent elective limb surgery under fentanyl or Innovaranaesthesia. End-tidal and mixed venous PCO₂ were increasedsignificantly in the first 150 min after the last dose of drug(P<0.001, P<0.01). but had returned to control valuesby 4 h. Ventilation and ventilatory response to carbon dioxidewere significantly depressed in all patients (P < 0.001),but returned to near control values at 4 h. Fentanyl and Innovaranaesthesia displaced the carbon dioxide response to the right,but no correlation was found between either the magnitude ofthe displacement of the response curve or the alteration inslope and the control values. This suggests that patients witha low value of VI/Pco₂ are not more susceptible to the ventilatorydepressant action of narcotic anaesthetics. Recovery of ventilatoryresponsiveness towards normal during the 4 h after anaesthesia,occurred in a graded and progressive manner; there was no evidenceof a biphasic pattern of recovery. ^*Present address: Centre for Advanced Studies in Health Sciences,Western Australian Institute of Technology, Bentley, WesternAustralia. Presented to the annual meeting of the Canadian AnaesthetistsSociety, Ottawa, Ontario, June 1978.