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PubMed1983

[Epidemiology and basic pathogenetic mechanisms of environmental and iatrogenic diseases].

In the first part environmental diseases by air pollution, water contamination and dietary factors are discussed. The important role of the combustion of coal and petrol and the increasing confrontation with carcinogenic substances, especially with those originated by smoking of tobacco are stressed and underlined by epidemiologic dates. Other epidemiologic evidences are mentioned concerning the development of cardiovascular diseases, neoplastic diseases of the colon or liver diseases by dietetic factors. In the second part epidemiologic facts of drug induced reactions and iatrogenic cases of death in hospitalized and out-patients are reported. The main responsible pathogenetic factors for such events, prevailing in elder persons, are seen in the reduced hepatic metabolic capacity, the decreasing tubular or glomerular function of the kidneys and above all the different and often unpredictable drug interactions. The most important pathogenetic mechanisms for drug interactions are changes of drug binding to albumin or competitive disturbance of renal excretion and particularly alterations of the biotransformation processes as enzyme induction or enzyme inhibition. The clinical relevance of these theoretical considerations is demonstrated by some practical examples referring to the importance of a solid knowledge of the many possible interactions in drug therapy especially in elder patients.

Aged↗
PubMedDate not supplied

[Drug interactions involving psychotropic agents and anticonvulsants].

The problem of drug interactions is particularly important for psychoactive agents and for anticonvulsants because of their large use and of peculiarities of their clinical application. Such interactions may, in a few conditions, explain unforeseen adverse effects, and, more frequently, they disturb the meaning of plasma determinations of the monitored drugs. Some interactions can be pharmacokinetic, principally by way of enzyme induction or enzyme inhibition, and than they lead to disturbances in the plasma levels of the active substances. On the other hand, interactions can take place at the pharmacodynamic level, which is as an important condition although it is less well-known. Some examples are given for both mechanisms.

Anticonvulsants↗
PubMed1985

Specificity of induction of cancer protective enzymes by analogues of tert-butyl-4-hydroxyanisole (BHA).

Protection by 2(3)-tert-butyl-4-hydroxyanisole (BHA) and related phenols against chemical carcinogens, mutagens and other toxins has been attributed to the elevation of tissue levels of non-oxygenative detoxification enzymes. To analyze the mechanisms and specificity of these enzyme inductions, we synthesized a series of mono- and dialkyl ethers of tert-butylhydroquinone (R1O-[(CH3)3C-C6H3]-OR2) and its dimer. The abilities of these compounds to elevate the cytosolic specific activities of glutathione S-transferases (measured with 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene) and of NAD(P)H: quinone reductase in liver, upper small intestine and forestomach of female CD-1 mice were evaluated. The animals were fed five daily doses of 50 mumoles of each monomer (or 25 mumoles of each dimer). The structures of the monomers examined were: R1 = H and R2 = CH3 (I), R2 = C2H5 (VI), R2 = (CH2)2CH3 (VIII), R2 = CH(CH3)2 (X); R1 = CH3 and R2 = C2H5 (VII), R2 = (CH2)2CH3 (IX), R2 = CH(CH3)2(XI); R2 = CH3 and R1 = C2H5(III), R1 = (CH2)2CH3(IV) and R1 = CH(CH3)2 (V). In addition, the monomethyl (XIII), monoethyl (XIV) and mono-n-propyl (XV) ethers of BHA dimer (XII; 2,2'-dihydroxy-3,3'-di-tert-butyl-5,5'-dimethoxybiphenyl) were also prepared. Under the conditions tested, all compounds were ineffective as enzyme inducers in the forestomach but produced coordinate induction of enzymes (generally 2- to 6-fold) in the cytosols of liver and mucosa of proximal small intestine. Increases in bulk of R1 and R2 beyond methyl groups tended to decrease the inductive potency of both monomers and dimers. The lack of strict structural specificity suggests that the induction depends on metabolic conversion of the analogues to common types of metabolites.

Animals↗
PubMed1979

Induction of enzyme activity in cell culture: a rapid screen for detection of planar polychlorinated organic compounds.

Induction of aryl hydrocarbon hydroxylase (AHH) activity in rat hepatoma cell line serves as a simple and rapid method to detect minute (pg) amounts of certain classes of compounds, e.g., dibenzo-p-dioxins, dibenzofurans, and biphenyls. This method may provide a quick screen for such substances in extracts from foods prior to chemical identification. AHH activity is measured by conversion of benzo[a]pyrene (BP) to 3-hydroxy BP in homogenized cell extracts from control and treated cultures and is reported as pmol product formed/mg protein/min. Substances screened by this method include polyhalogenated analogs of dibenzo-p-dioxin (24 compounds), dibenzofuran (11 compounds), biphenyl (7 compounds), and extracts from several food sources. Response of the most reactive compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was used to prepare a standard curve, and the AHH activity induced by mole doses of test substance is reported as an ED50 response (the estimated dose needed to produce 50% maximum enzyme induction). The AHH activity induced by food extracts is equated to the standard curve and reported as TCDD equivalents. A potent ED50 response in cell culture appears to correlate well with known toxic responses in other mammalian and avian systems for certain test substances. This correlation suggests that the cell culture enzyme induction method is a useful model for screening food extracts that are suspected to be contaminated with polychlorinated planar substances. A collaborative study would demonstrate the reproducibility of the method.

Animals↗
PubMedDate not supplied

Effects of long-term phenobarbital treatment on the liver in dogs.

Long-term administration of phenobarbital has been reported to cause hepatic injury in dogs. Phenobarbital induces hepatic enzymes, and it may be difficult to distinguish the effect of enzyme induction on serum liver enzyme activities from actual hepatic damage. The hepatotoxicity of phenobarbital and the impact of enzyme induction on serum liver enzyme activity were investigated prospectively in 12 normal dogs. Phenobarbital was administered for 29 weeks at 5 mg per kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h, resulting in therapeutic serum phenobarbital concentrations (20-40 microg/mL). Serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), fasted bile acids (fBA), total bilirubin, and albumin were determined before and during treatment. Lateral abdominal radiographs, abdominal ultrasounds, and histopathologic examinations of liver tissue obtained by ultrasound-guided biopsy were performed before and during treatment. Radiographs revealed a moderate increase in liver size in most dogs. Ultrasonographic examination revealed no change in liver echogenicity or architecture. No evidence of morphologic liver damage was observed histopathologically. ALP and ALT increased significantly (P < .05), GGT increased transiently, and albumin decreased transiently during the study. There were no significant changes in AST, bilirubin, and fBA. These results suggest that increases in serum ALP, ALT, and GGT may reflect enzyme induction rather than hepatic injury during phenobarbital treatment in dogs. Serum AST, fBA, and bilirubin, and ultrasonographic evaluation of the liver are not affected by the enzyme-inducing effect of phenobarbital and can therefore be helpful to assess liver disease in dogs treated with the drug.

Administration, Oral↗
PubMed1986

Expression of intracellular biochemical defects of lymphocytes in aging: proposal of a general aging mechanism which is not cell-specific.

There is a decline in immune capacity with age which is expressed on the organismic level by association with numerous immune-related diseases, on the cellular level by impaired mitogenesis, on the biochemical level by impaired metabolic pathways, and on the molecular level by decreased protein synthesis and degradation. Defects in various cofactors such as calcium and several nucleotides also occur and may be related to the impaired enzyme function during mitogenesis in the aged. The central cause for decreased mitogenesis in the aged could be a decrease in protein synthesis which appears to cause impaired enzyme induction. This impaired enzyme induction accounts in part for the decreased glycolytic flux and DNA synthesis in these cells. Decreased protein synthesis also has been associated with a decreased synthesis of lymphokines which help these cells to proliferate. Numerous other intracellular age-related defects of lymphocytes also occur which may collectively play important interdependent roles in the impaired lymphocyte function of the aged. A potential general underlying mechanism of cellular senescence is proposed based on a genetic "slowing-cycle" effect of transcription, translation, and enzyme induction with immunosenescence presented as an example of an expression of these basic defects.

Aging↗
PubMed1993

Cytochrome P450 2B enzyme (CYP2B) induction defect following phenobarbital treatment in the fa/fa Zucker rat: molecular characterization.

The present study describes the mechanism of the dampened induction of the CYP2B1 and CYP2B2 genes following phenobarbital treatment in the phenotypically obese fa/fa Zucker rat. The fa/fa Zucker rat demonstrated a threefold lower level of CYP2B1/2B2 enzyme induction, as indicated by reduced testosterone oxidation at the 16 beta position and resorufin formation from pentoxy- and benzyloxyresorufin, protein concentration (Western blot analysis), and steady-state mRNA levels (Northern and slot blot analyses) following in vivo treatment with phenobarbital than the Fa/? littermate controls. A primary hepatocyte cell culture system was used to determine if the dampened induction of the CYP2B1/2B2 enzyme is dependent on hormonal influences. Phenobarbital-treated (0.75 mM) hepatocytes from fa/fa Zucker rats showed approximately a three-fold lower induction response based on measurements of CYP2B1/2B2 (R-17 cDNA probe) and CYP2B1 (oligo probe) mRNAs. In order to evaluate whether this dampened response was at the level of transcriptional activation or initiation, as opposed to altered message stability, we measured the rate of transcription of CYP2B1/2B2 genes in nuclei from cultured hepatocytes during run-off experiments. Compared to Fa/? controls, the fa/fa Zucker rat had a greater than threefold lower nuclear transcription rate of CYP2B1/2B2 mRNA. These results suggest that the defective induction of the CYP2B1 and CYP2B2 genes exists at the transcriptional level in the mutant obese fa/fa Zucker rat. These data provide strong evidence that at least two genes are involved. Multiple gene involvement would suggest that the defect is not due to a mutation of the CYP2B gene cis-acting sequence. Instead, the lack of binding of a trans-acting factor, the presence of a repressor, or a defect in transcriptional activation is more likely the molecular mechanism(s) for this enzyme induction defect.

Animals↗
PubMedDate not supplied

[Kinetic resonance in open biochemical reactions with genetic induction of enzyme biosynthesis].

It has been shown that the genetic induction of enzyme synthesis by the substrate, like the kinetic induction, may bring about resonance responses in an open biochemical reaction at periodic external disturbances. Joint action of genetic and kinetic inductions broadens the range of the system parameters, where the resonance phenomena are possible. Under the joint action of genetic and kinetic inductions the resonance frequency may be independent of the amplitude of external periodic disturbance.

Enzyme Induction↗
PubMedDate not supplied

Mercurials and dimercaptans: synergism in the induction of chemoprotective enzymes.

The induction of NAD(P)H:quinone reductase (EC 1.6.99.2; QR) in Hepa 1c1c7 murine hepatoma cells provides a versatile quantitative model for measuring the potencies of inducers for Phase 2 detoxication enzymes. Since many inducers of these enzymes also protect animals and their cells against the toxic and neoplastic effects of carcinogens, understanding the mechanisms of induction of Phase 2 enzymes is important. Both HgCl2 and 2,3-dimercaptopropanol (BAL) are inducers of QR in these cells, and paradoxically BAL (which is about 30 times less potent than HgCl2) enhances the inducer potency of HgCl2 substantially. This synergism depends on the presence of two thiol groups on adjacent carbon atoms. Since nonchelated mercury(II)-thiol compounds did not show synergism, the formation of very high affinity bidentate chelates appears to be essential for such synergism. A major mechanism for the augmentation of the inducer potency of mercury(II) by BAL is the more rapid cellular uptake and the accumulation of higher intracellular concentrations of mercury. It is also possible that BAL-mercury chelates are intrinsically more potent as inducers. Although equimolar mixtures of BAL and HgCl2 and the synthetic chelate isolated from such mixtures were more potent inducers than HgCl2 alone, the presence of excess BAL increased this inducer synergism even further. By chromatography we showed the reversible formation of higher order complexes between BAL and mercury(II). Such complexes are transported into cells more efficiently and appear to be more potent than free HgCl2 or the chelate obtained from equimolar mixtures of BAL and HgCl2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Factors contributing to the accelerated clearance of theophylline and antipyrine in adults with exocrine pancreatic disease.

1. Oxidative drug metabolizing capacity has been assessed by oral antipyrine and/or theophylline tests in consecutive patients with chronic pancreatitis (CP; alcoholic 24, idiopathic 47), acute pancreatitis (AP; 28) and pancreatic cancer (CA; 11). Most of the patients had drastically reduced their alcohol consumption and dietary fat intake for variable periods before the tests. Excellent bioavailability of theophylline was confirmed from paired oral and intravenous tests in seven subjects, including two with exocrine pancreatic failure. 2. The clearance of theophylline in the patients was faster than in 15 controls with a 'healthy lifestyle' [median 104 (range 18-320) ml h-1 kg-1 vs median 68 (range 50-97) ml h-1 kg-1, P less than 0.01]. The difference was especially apparent in the groups with alcoholic CP (P less than 0.001 and idiopathic CP (P less than 0.01), but not in the AP and CA group as a whole, although drug clearance in some 50% of those cases exceeded the reference range. 3. There was good correlation between theophylline and antipyrine clearance in a subset of 91 subjects who had both tests (15 controls, 76 patients), but antipyrine was much less sensitive as a marker of enzyme induction. This suggests that enzyme induction in pancreatic disease preferentially involves the polycyclic aromatic hydrocarbon-inducible subfamily of cytochrome P-450. 4. The lack of correlation between pancreatic secretory capacity in 56 cases, judged by a secretin-pancreozymin test, and theophylline clearance suggests that enzyme induction is not secondary to pancreatic dysfunction. 5. Multivariate regression analysis identified approximately 50% of variability in clearance of each probe.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Dose-response relationships for initiation of rat liver tumours by diethylnitrosamine and promotion by phenobarbitone or alcohol.

Small doses of initiators, such as the nitrosamines, are present in the diet and man is also exposed to promoters, such as phenobarbitone or alcohol. A simple two-stage model of rat hepatocarcinogenesis with a single ip dose of diethylnitrosamine (DEN) as the initiator and sodium phenobarbitone or ethanol given in the drinking-water for 12-18 months as the promoter was used to investigate dose-response relationships for initiation and promotion. Phenobarbitone given alone for 12 months had no carcinogenic effect on rat liver. Low doses of DEN, given prior to phenobarbitone promotion, resulted in the formation of hyperplastic nodules, but only the high dose of DEN (30 mg/kg) resulted in carcinoma formation. Basophilic foci showed a dose-response relationship with DEN and it is suggested that these may be more important than nodules in carcinoma formation and that they represent a heterogeneous group. Only the top concentration of phenobarbitone (1000 micrograms/ml) promoted carcinoma initiated by 30 mg DEN/kg although lower doses of phenobarbitone produce significant enzyme induction. A weak enzyme inducer, 5% ethanol, was as effective a promoter as 1000 micrograms phenobarbitone/ml. Enzyme induction and tumour formation are therefore not directly related. Commencing top-dose phenobarbitone promotion 10 months after the single dose of DEN led to tumour formation, demonstrating the persistence of DEN-initiated cells. The significance to man of the apparent thresholds for tumour initiation and promotion is discussed.

Animals↗
PubMed1987

An in vitro model for the induction of angiotensin-converting enzyme in sarcoidosis. Evidence for a soluble ACE-inducing factor.

Normal peripheral blood T-lymphocytes (T) enhance monocyte (Mo) angiotensin converting enzyme (ACE) production in vitro. To evaluate the possible role of a soluble mediator in enzyme induction, the ability of conditioned medium (CM) from Mo-T cocultures to stimulate ACE in fresh Mo was examined. These studies demonstrated that CM promoted a dose-dependent increase in ACE. Generation of the active factor required both Mo and T during culture since neither cell alone yielded active CM. Time course studies revealed that the ACE-inducing activity appeared in CM after 3 to 4 days of culture and increased steadily thereafter. The CM effectively induced ACE in Mo from several donors in contrast to T-dependent induction, which required autologous conditions. The time courses for T-dependent and CM-dependent ACE induction were similar, and the results suggested that the Mo must go through some period of maturation before they respond to CM. We conclude that a soluble mediator derived from Mo-T cocultures enhances Mo ACE production. This in vitro system may be a useful experimental model of the in vivo induction of ACE in the Mo-derived sarcoid epithelioid cell.

Cell Communication↗
PubMed1984

An investigation of the effects of phenobarbitone on the pharmacokinetics of norethindrone in the rat using liver perfusion and everted gut sacs.

Previous in vivo studies have suggested that phenobarbitone increases the first pass clearance of norethindrone in the rat by induction of enzymes both in the gut wall and liver. In the present study phenobarbitone caused an increase in both the production of highly polar ether-extractable metabolites and the conjugation of the steroid as it crossed the wall of the everted gut sac preparation. In addition, there was a marked increase in the uptake of norethindrone into the liver followed by increased phase I metabolism in the isolated perfused liver. As expected for a highly cleared drug, enzyme induction had no measurable effect on the terminal half-life of norethindrone in the perfused liver preparation.

Animals↗