Induction of UDP glucuronyltransferase in the liver and extrahepatic organs of the rat
Abstract
UDP glucuronyltransferase (4-methylumbelliferone) activity was enhanced in the liver of the rat after administering phenobarbital, cinchophen or 3-methylcholanthrene, in the lung after administration of cinchophen or 3-methylcholanthrene, and in the kidney after cinchophen. The UDP glucuronyltransferase of the spleen could not be induced with the dosage of the drugs used. Chlorpromazine was not able to induce either hepatic or extrahepatic UDP glucuronyltransferase. Chlorpromazine competitively inhibited hepatic UDP glucuronyltransferase .
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The influence of flow on the metabolism of perfused benzo[a]pyrene by isolated rat lung
1983, Chemico-Biological InteractionsIn order to investigate the influence of flow and, thus, substrate delivery, on the ability of lung to metabolize foreign compounds, the disappearance of circulating [3H]benzo[a]pyrene ([3H]B[a]P) and the appearance of B[a]P metabolites was monitored in isolated rat lungs from control and 3-methylcholanthrene (3-MC) pretreated rats perfused at low (10 ml/min) and high (45 ml/min) flows. Increasing the flow or 3-MC pretreatment hastened the disappearance of B[a]P from the perfusion medium reservoir and increased the rate of appearance of total metabolites. However, these manipulations affected the appearance of individual metabolites in the medium in different ways. For example, in lungs from control rats the rate of appearance of 7,8-dihydrodiol (7,8-dihydroxy-7,8-dihydro-B[a]P) (7,8-DHD) in the perfusion medium was markedly increased by increasing flow while that of B[a]P-1,6-quinone was minimally affected. In addition, increasing flow increased the concentration of some B[a]P metabolites, such as 4,5-dihydrodiol (4,5-dihydroxy-4,5-dihydro-B[a]P) (4,5-DHD) in the lung tissue of control rats at the end of the perfusion period, but did not effect much change in the concentration of these metabolites in lungs from 3-MC-pretreated rats. The results show that flow, as well as 3-MC pretreatment, may alter the rate at which metabolism of foreign compounds occurs and the temporal profile of metabolites produced by the intact lung.
The effect of aroclor 1254 pretreatment on the phase I and phase II metabolism of 7-ethoxycoumarin in isolated viable rat kidney cells
1981, Biochemical PharmacologyThe metabolism of 7-ethoxy-and 7-hydroxy-coumarin was studied in viable kidney cortex cells isolated from control and Aroclor 1254-pretreated rats. Such pretreatment led to induction of the microsomal mono-oxygenase-mediated Phase I system but did not produce induction of Phase II glucuronidation or sulphation activity. Induction of the microsomal mono-oxygenase system led to an increase in the amount of unconjugated Phase I metabolite present during sequential Phase I and Phase II metabolism. It is suggested that this increase is due to some form of ‘uncoupling’ of the microsomal mono-oxygenase and glucuronidation systems.
Metabolism of drugs by the kidney
1980, Kidney InternationalThe kidneys have many clearly defined physiologic functions. Although their role as an excretory organ for drugs and chemicals and their polar metabolites is well described, their involvement in the biotransformation of xenobiotics is relatively poorly understood. It is accurate to state that our present understanding of the metabolic processes of drugs is based largely on studies carried out in the liver. Only recently have detailed investigations into drug metabolism in the kidney been carried out. These studies have shown that the kidney is meta-bolically very active in effecting the biotransformation of a variety of chemicals and drugs and, in some cases, surpasses the liver.
It is important to understand the role of the kidney in drug and chemical biotransformation for a variety of reasons. Because the kidney receives a substantial portion of the cardiac output, it is reasonable to expect that it may make a significant contribution to the total metabolic alteration of drugs in the body. Furthermore, it is now known that the toxic effects of many drugs and chemicals are attributable to their metabolic conversion to reactive electrophilic intermediates, which, on reaction with cellular nucleophiles, lead to a variety of deleterious effects. Perhaps most important is the appreciation that this interaction between reactive intermediates and critical cellular macromolecules is intimately involved in mutagenic and carcinogenic changes. In addition, necrotic changes may also be associated with cellular alkylation. Thus, a complete perspective on the role of the kidney in pharmacologic and toxicologic processes is dependent on a thorough understanding of the drug and chemical metabolic capabilities of this organ.
The biotransformation of organic compounds can be conveniently divided into oxidative, reductive, hydrolytic, and synthetic or conjugation reactions. The first three reactions are based on the type of chemical change produced. Synthetic or conjugation reactions usually involve the enzyme-catalyzed combination of a chemical or a metabolite and a carbohydrate or an amino acid, and they yield highly polar, readily excretable metabolites. Furthermore, multiple metabolic alterations are very common. Williams, in his classic book, Detoxication Mechanisms, suggests that the metabolism of many xenobiotics occurs in two steps [1]. The first, termed “phase I reactions,” includes oxidative, reductive, and hydrolytic reactions; the second, termed “phase II reactions,” consists of conjugative reactions and includes, for example, glucuronide, sulfate, and hippuric acid formation. It should be noted that although the metabolites produced in phase I reactions are frequently less toxic or less active pharmacologically than the parent compound is, abundant examples can be cited where the metabolites are more toxic and more active pharmacologically. By the same token, although the conjugates produced in phase II reactions are usually very polar and less toxic, notable exceptions exist; for example, the sulfate conjugate of N-hydroxyacetyl-aminofluorene is thought to be the proximate carcinogen in the case of this compound [5].
Enhanced disappearance of drugs from plasma following polybrominated biphenyls
1977, Toxicology and Applied PharmacologyPolybrominated biphenyls (PBBs) are potent stimulators of hepatic drug metabolism. The purpose of this investigation was to determine the effect of dietary exposure to PBBs on the disappearance of drugs from plasma in mice. To estimate hepatic function, plasma and hepatic concentrations of indocyanine green (ICG) and ouabain were determined at various times following intravenous injection of these drugs (ICG, 40 mg/kg; ouabain, 0.1 mg/kg). Two-week dietary exposure to PBBs did not affect body weight but resulted in a dose-dependent increase in liver weight. Plasma concentrations of ICG were significantly lower than control values 10 and 15 min following injection of ICG in mice fed 100, 150, and 200 ppm of PBBs. In addition, 60-min plasma ouabain concentrations in 100- and 200-ppm PBBs-fed mice were significantly lower than control values. PBBs induced enhanced disappearance of ICG from plasma correlated to significantly higher hepatic ICG content. This effect was similar to that produced by phenobarbital pretreatment (75 mg/kg/day for 4 days) in mice. When compared to controls, mice fed PBBs had significantly higher hepatic ouabain content 10 min following glycoside injection but significantly lower amounts in liver 30 and 60 min following injection. PBBs feeding did not alter ouabain LD50 values. These results demonstrate that PBBs enhance drug elimination from plasma.
Development of bilirubin transport and metabolismin the newborn rhesus monkey
1977, The Journal of PediatricsHepatic transport and metabolism of bilirubin have been examined in term, premature, and postmaturenewborn Macaca mulatta (rhesus) monkeys with and without prior phenobarbital treatment of pregnant mother and neonate. In untreated neonates a biphasic pattern of physiologic unconjugated hyperbilirubinemia has been observed. Phase I was characterized by a rapid increase in serum bilirubin concentration to 4.5 mg/dl by 19 hours and an equally rapid decline to 1.0 mg/dl by 48 hours of age. Phase II was characterized by a stable elevation at 1.0 mg/dl (four times greater than in the adult) from 48 to 96 hours of age, followed by a decline to normal adult concentrations thereafter. An identical pattern was observed in 29 normal, term human neonates, but the duration of each phase was approximately three times as long as that in the monkey. Phase I hyperbilirubinemia appears to result from a sixfold increase in bilirubin load presented to the liver in the neonatal period, combined with marked deficiency in hepatic bilirubin conjugation, the rate-limiting step during Phase I. Hepatic uptake of bilirubin is not rate limiting during Phase I but may contribute to Phase II hyperbilirubinemia. An increased bilirubin load persists throughout the first 19 days of life in the monkey. Phase I physiologic jaundice in the monkey neonate was completely eliminated by prenatal maternal and neonatal administration of phenobarbital. A threefold enhancement of hepatic conjugation of bilirubin (glucuronyl transferase activity) during Phase I entirely accounted for the prevention of hyperbilirubinemia. The bilirubin load was unaffected by administration of phenobarbital. Whereas in control neonates the bilirubin load slightly exceeded hepatic bilirubin conjugating capacity and resulted in retention of bilirubin, in phenobarbital-treated neonates, hepatic conjugating capacity slightly exceeded that required for the bilirubin load. Administration of phenobarbital failed to alter Phase II hyperbilirubinemia and did
Glucuronide synthesis in the isolated perfused rat lung
1976, Biochemical Pharmacology