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PubMed2005

Clinical enzymology: an autobiographical history.

In this paper, I review the origins of Clinical Enzymology with special emphasis on the years between 1960 and 1980 when the greatest advances in the subject took place. These are described in relation to my own research interests and contributions, focusing upon subclinical hepatic damage caused by viral infection and by alcohol; myocardial infarction; detection of cervical carcinoma by vaginal fluid analysis; evaluation of pancreatic function; and the clinical implications of microsomal enzyme induction. Reasons are proposed for the failure of enzymology to attain the status of an autonomous medical specialty, in contrast to the success of similar fields of knowledge that grew up in the same era.

Enzyme Induction↗
PubMed1980

Considerations in the selection and use of chemicals within the animal facility.

Chemicals are important and unavoidable parameters in the milieu of the laboratory animal used in biomedical research today. Examples of chemicals used include detergents and sanitizing agents. Detergents are used to remove dirt while sanitizing compounds, such as germicidal agents, decrease bacteria, fungi or viruses in the facility. The types used (that is, phenols, alcohols, oxidizing agents) depend upon the degree of cleanliness and the sanitizing properties desired and vary for germfree, specific pathogen-free and conventional animal facilities. Chemicals are routinely added to water to control bacteria in mouse facilities. Similarly, insecticides and pesticides are used to reduce the number of vermin in animal and feed rooms. Also, the bedding may contain chemicals (that is, cedrene and cedral in red cedar shavings). These and other chemicals in the vivarium may influence enzyme induction or inhibition, may result in increased or decreased toxicity, may alter the function or metabolism of organs and can thereby alter the outcome of animal experiments.

Animal Husbandry↗
PubMed2002

Structure-activity relationships on phenylalanine-containing inhibitors of histone deacetylase: in vitro enzyme inhibition, induction of differentiation, and inhibition of proliferation in Friend leukemic cells.

Inhibitors of histone deacetylases (HDACs) are a new class of anticancer agents that affect gene regulation. We had previously reported the first simple synthetic HDAC inhibitors with in vitro activity at submicromolar concentrations. Here, we present structure-activity data on modifications of a phenylalanine-containing lead compound including amino acid amides as well as variations of the amino acid part. The compounds were tested for inhibition of maize HD-2, rat liver HDAC, and for the induction of terminal cell differentiation and inhibition of proliferation in Friend leukemic cells. In the amide series, in vitro inhibition was potentiated up to 15-fold, but the potential to induce cell differentiation decreased. Interestingly, an HDAC class selectivity was indicated among some of these amides. In the amino acid methyl ester series, a biphenylalanine derivative was identified as a good enzyme inhibitor, which blocks proliferation in the submicromolar range and is also a potent inducer of terminal cell differentiation.

Acetylation↗
PubMed1990

[D-glucaric acid. A new method proposed to investigate damage from exposure to anesthetic gas and vapors].

Acute exposure and hepatotoxicity following full anesthetic doses is controversial, despite various experimental trials. On the other hand, microsomial enzyme induction following the chronic use of anesthetic gases and vapours, even with minimal metabolism, has been established. Therefore, there is increasing interest in the field of prevention to develop techniques and instruments to minimize pollution of anesthetic vapours and screening methods to detect early liver-damage. We have evaluated the reliability of D-Glucaric Acid test in monitoring microsomial enzyme induction after anesthesia. We evaluated urinary excretion of D-Glucaric Acid before and after exposure to anesthetic gases in 53 subjects, including medical personnel and patients. Statistical analysis of these data confirm the usefulness of this technique to assess acute liver damage in patients undergoing general anesthesia (postoperative increase of 10.5 microns/l as average value of urinary acid excretion, chi 2 = 9.8; p less than 0.01). This technique is also valuable in demonstrating damage in operating room personnel due to chronic exposure (base values greater than 12 microns/l in anesthesiologists with a 9 microns/l increase at the end of surgical intervention, chi 2 = 8.1; p less than 0.01). Data of patients submitted to local anesthesia are more difficult to interprete. They presented a decrease in acid urinary excretion (less than 10 microns/l; chi 2 = 1.93; p less than 0.2) probably due to hemodynamic changes which occurred during spinal block or due to degree of sedation related to de-afferentation itself.

Adult↗
PubMed1984

Prediction of metabolic drug interactions involving beta-adrenoceptor blocking drugs.

There is evidence, from human and animal studies, that drug-metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific, substrate requirements. Consequently drug interactions may arise when two drugs bind to the same enzyme. The degree of enzyme inhibition will be partly dependent on the relative affinities of the drugs for the enzyme and on their rates of turnover. The decrease in drug clearance produced by enzyme inhibition is dependent on the fraction of the drug normally metabolised by the inhibited pathway(s). Cimetidine, a P-450 enzyme inhibitor, increases the systemic bioavailability of propranolol and labetalol, which undergo extensive metabolism, but does not affect the clearance of atenolol, which is excreted largely unchanged. In this situation, both the extent and type of biotransformation are important. Thus, cimetidine has no effect on the clearance of penbutolol, even though the drug is eliminated almost entirely by biotransformation. The major metabolite is penbutolol glucuronide, and it has been shown recently that cimetidine does not inhibit glucuronylation. Beta-adrenoceptor blockers also act as enzyme inhibitors themselves. For example, antipyrine clearance is decreased by propranolol and to a lesser extent by metoprolol, whereas atenolol has no effect. It has been suggested, therefore, that there is a relationship between the lipid-solubility of beta-adrenoceptor blockers and their ability to inhibit drug metabolism. The clearance of lipophilic beta-adrenoceptor blockers is dependent on hepatic enzyme activity, and is therefore sensitive to enzyme induction. For drugs with high hepatic clearance and subsequent high presystemic elimination, a moderate increase in the extraction ratio will produce a marked decrease in systemic bioavailability. (ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1987

The effect of midazolam administration on the pharmacokinetics of antipyrine in the rat.

1. The clearance and elimination half-lives for i.v. doses of antipyrine were determined in 6 groups of 6 male CD rats with no prior treatment, then again following 7 days treatment with graded oral doses of midazolam, and finally after 3 i.p. doses of phenobarbitone. 2. Substantial increases in clearance and decreases in half-lives were observed following phenobarbitone treatment, demonstrating that antipyrine provides a reliable index of enzyme induction. 3. After treatment with midazolam, maximal induction was seen in animals dosed at 27 or 80 mg/kg per day; an intermediate effect was found with 9 mg/kg per day and no effect at 0.2 and 1.0 mg/kg per day. 4. The results indicate that there is a substantial margin of safety between the proposed human therapeutic doses (7.5 to 15 mg/day) and the minimum effective dose that leads to enzyme induction in laboratory animals.

Animals↗
PubMed1988

Ethosuximide disposition kinetics in rats.

1. Single and multiple dose disposition kinetics of ethosuximide were studied in male Sprague-Dawley rats following intravenous administration. 2. The plasma disappearance of a single 35 mg/kg dose followed for 75 h was not linear. A dose-ranging study suggested that the apparent non-linearity of ethosuximide's plasma disappearance might be due to enzyme induction over time with the drug exhibiting a faster elimination from 24 h onward. 3. Ethosuximide, after only two daily doses of 35 mg/kg/day, shortened pentobarbital-induced sleep in rats. The clearance of ethosuximide was also significantly faster after four daily 35 mg/kg doses than after a single 35 mg/kg dose. 4. Single sample clearance estimates calculated from ethosuximide concentrations prior to enzyme induction, viz. up to 24 h post-dose, were practically identical to multiple sample clearance values. Both single and multiple sample clearances were calculated assuming linear rather than non-linear elimination.

Animals↗
PubMed2006

Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions.

The human transcription factor pregnane X receptor (hPXR) is a key regulator of enzyme expression, especially cytochrome P450 3A4 (CYP3A4). Due to the prominence of CYP3A4 in the elimination of many drugs, the development of high throughput in vitro models to predict the effect of drugs on CYP3A4 expression have increased. To better interpret and predict potential drug-drug interactions due to CYP3A4 enzyme induction, we evaluated 170 xenobiotics in a hPXR transactivation assay and compared these results to known clinical drug-drug interactions. Of the 170 xenobiotics tested, 54% of them demonstrated some level of hPXR transactivation. By taking into consideration cell culture conditions (solubility, cytotoxicity, appropriate drug concentration in media), as well as in vivo pharmacokinetics (therapeutic plasma C(max), distribution, route of administration, dosing regimen, liver exposure, potential to inhibit CYP3A4), the risk potential of CYP3A4 enzyme induction for most compounds reduced dramatically. By employing this overall interpretation strategy, the final percentage of compounds predicted to significantly induce CYP3A4 reduced to 5%, all of which are known to cause drug-drug interactions. Also, this is the first report that identifies several potent compounds that have the ability to transactivate hPXR that previously have not been identified, such as terbinafine, diclofenac, sildenafil, glimepiride, montelukast, and ticlopidine.

Biological Assay↗
PubMed2004

Isoforms of serum gamma-glutamyltransferase in epileptic patients treated with enzyme-inducing anticonvulsant drugs.

PURPOSE: The increase of serum activity of gamma-glutamyltranferase (gammaGT) through the action of enzyme-inducing anticonvulsant drugs has been widely documented; however, the behaviour of its multiple forms and its relationship with the degree of enzyme induction has received little coverage. This subject is the major aim of our paper. METHODS: An electrophoretic study of the serum gammaGT isoforms was made in 90 adult epileptic patients under chronic treatment with phenobarbital, phenytoin and carbamazepine in polytherapy. RESULTS: A significant correlation was found (p<0.001) between the drug score and urinary excretion of D-glucaric acid (DGA) (r=0.773), total gammaGT (r=0.382), gammaGT1 (r=0.398) and gammaGT2 (r=0.361). In a group of 11 patients with the gammaGT3 isoforms, considered a sensitive test for cholestasis, serum activities of total gammaGT, gammaGT1, gammaGT2 and 5 -nucleotidase were found that were significantly higher than in the 79 patients without the gammaGT3 isoform (p<0.001); however, for the drug score and excretion of DGA, no significant differences were found, suggesting a similar degree of enzyme induction in both groups of patients. CONCLUSIONS: The presence of cholestasis, at least biochemically detectable in some of these patients, appears to be a factor of paramount importance when interpreting the effect of enzyme-inducing anticonvulsant drugs on serum gammaGT. This fact may contribute towards explaining its highly varied response to the administration of these drugs.

Adult↗
PubMed1989

beta-Lactamase stability and in vitro activity of oral cephalosporins against strains possessing well-characterized mechanisms of resistance.

The in vitro activity of four oral cephalosporins was assessed in dilution tests with 50 isolates of the family Enterobacteriaceae possessing well-characterized mechanisms of resistance to beta-lactam antibiotics. The interaction of the drugs with a broad array of beta-lactamases was also determined in spectrophotometric assays and tests for enzyme induction. Overall, the percentages of strains susceptible to each of the study drugs were 82% for cefixime, 62% for cefuroxime, 58% for cephalexin, and 44% for cefaclor. The poor activity of the older cephalosporins was due to a high degree of susceptibility to hydrolysis by both plasmid-mediated and chromosomally mediated beta-lactamases. For cefaclor, higher MICs were associated with higher levels of plasmid-mediated beta-lactamases in the strains. Resistance to cefuroxime was seen primarily among strains expressing high levels of class I or IV beta-lactamase. Resistance to cefixime was seen only among strains expressing high levels of class I enzymes. Neither cefixime nor cefuroxime was a strong inducer of class I beta-lactamases, although enzyme induction did appear to play a role in cefuroxime resistance in a strain of Serratia marcescens. The consistently greater activity of cefixime over cefuroxime was found not to be due to greater drug permeation into the cell. Rather, it appeared to result from the high affinity of the drug for target enzymes.

Anti-Bacterial Agents↗
PubMed1984

Polyamine metabolism and its relation to response of the aleurone layers of barley seeds to gibberellic Acid.

Polyamine metabolism and its relation to the induction of alpha-amylase formation in the aleurone layers of barley seeds (Hordeum vulgare cv Himalaya) in response to gibberellic acid (GA(3)) has been investigated. A high-performance liquid chromatographic system has been employed for qualitative and quantitative analyses of putrescine (Put), cadaverine (Cad), spermidine (Spd), spermine (Spm), and agmatine (Agm).Active polyamine metabolism occurs in the aleurone cells of deembryonate barley half seeds during imbibition. The aleurone layers isolated from fully imbibed half seeds contain about 880 nanomoles of Put, 920 nanomoles of Spd, and 610 nanomoles of Spm as free form per gram tissue dry weight while the levels of Cad and Agm are relatively low. The polyamine levels do not change significantly in the aleurone layers in response to added GA(3) (1.5 micromolar) during the 8-hour lag period of the growth substance-induced formation of alpha-amylase. Also, the polyamine levels are not altered by the presence of abscisic acid (3 micromolar) which inhibits the enzyme induction by GA(3). Kinetic studies show that both applied [U-(14)C]ornithine and [U-(14)C]arginine are primarily incorporated into Put during 2 hours of incubation, but the incorporation is not significantly affected by added GA(3). Additionally, added GA(3) does not affect the uptake and turnover of [1,4-(14)C]Put, nor does it affect the conversion of Put --> Spd or Spd --> Spm. Treatment of the aleurone layers with GA(3) for 2 hours results in no significant changes in the total activities or the specific activities of ornithine decarboxylase and arginine decarboxylase.Experiments with polyamine synthesis inhibitors demonstrate that the level of Spd in the aleurone layers could be substantially reduced by the presence of methylglyoxal-bis(guanylhydrazone) (MGBG) during imbibition. MGBG treatment does not affect in vivo incorporation of [8-(14)C] adenosine into ATP. The lower the level of Spd the less alpha-amylase formation is induced by added GA(3). The reduction of GA(3)-induced alpha-amylase formation by MGBG treatment can be either completely or partially overcome by added Spd, depending upon the concentration of MGBG used in the imbibition medium. The results indicate that the early action of GA(3), with respect to induction of alpha-amylase formation in barley aleurone layers, appears to be not on polyamine metabolism. However, polyamines, particularly Spd, may be involved in regulation of the growth substance-dependent enzyme induction.

Journal Article↗
PubMed1978

Time-course of interaction between carbamazepine and clonazepam in normal man.

The applicability of a pharmacokinetic model for drug interactions by enzyme induction was tested by chronic dosing situation using carbamazepine (Tegretol) as the inducer and clonazepam (Clonopin) as the drug affected. Seven healthy subjects received one 1.0 mg clonazepam tablet once a day for 29 days and one 200 mg carbamazepine tablet once a day from days 8 to 29. Plasma levels of clonazepam were measured by electron-capture gas-liquid chromatography and those of carbamazepine and its epoxide metabolite by gas chromatographic-chemical ionization-mass spectrometry. Clonazepam plasma levels reached an initial steady-state by day 7 and declined to a lower steady-state over 5 to 15 days after additions of carbamazepine. The decrease in clonazepam levels ranged between 19% and 37%. Autoinduction of carbamazepine metabolism was also evident. Urinary excretion of D-glucaric acid increased 2- to 4-fold following carbamazepine administration (p less than 0.005). This increase provided additional evidence that the present interaction was due to enzyme induction. Experimental clonazepam levels were fitted to an induction pharmacokinetic model for multiple dosing with an exponentially increasing clearance. Induced half-lives of clonazepam (mean = 22.5 +/- 11.5 hr) were shorter (p less than 0.005) than control values (32.1 +/- 16.6 hr). Apparent enzyme(s) turnover half-lives ranged between 1 and 6 days.

Adult↗
PubMed2001

Coiled coil region of streptokinase gamma-domain is essential for plasminogen activation.

The specific functions of the amino acid residues in the streptokinase (SK) gamma-domain were analyzed by studying the interactions of human plasminogen (HPlg) and SK mutants prepared by charge-to-alanine mutagenesis. SK with mutations of groups of amino acids outside the coiled coil region of SK gamma-domain, SK(K278A,K279A,E281A,K282A), and SK(D360A,R363A) had similar HPlg activator activities as wild-type SK. However, significant changes of the functions of SK with mutations within the coiled coil region were observed. Both SK(D322A,R324A,D325A) and SK(R330A,D331A,K332A,K334A) had decreased amounts of complex formation with microplasminogen and failed to activate HPlg. SK(D328A,R330A) had a 21-fold reduced catalytic efficiency for HPlg activation. The studies of SK with single amino acid mutation to Ala demonstrate that Arg(324), Asp(325), Lys(332), and Lys(334) play important roles in the formation of a HPlg.SK complex. On the other hand, amino acid residues Asp(322), Asp(328), and Arg(330) of SK are involved in the virgin enzyme induction. Potential contact between Lys(332) of SK and Glu(623) of human microplasmin and strong interactions between Asp(328) and Lys(330), Asp(331) and Lys(334), and Asp(322) and Lys(334) of SK are noticed. These interactions are important in maintaining a coiled coil conformation. Therefore, we conclude that the coiled coil region of SK gamma-domain, SK(Leu(314)-Ala(342)), plays very important roles in HPlg activation by participating in virgin enzyme induction and stabilizing the activator complex.

Base Sequence↗
PubMed2005

Effect of antiepileptic drugs on the urinary excretion of porphyrins in non-porphyric subjects.

The action of some anticonvulsant drugs as the causal agents of attacks of acute porphyria has been widely documented in the literature. However, little attention has been paid to the effect of these drugs on the urinary excretion of porphyrins in non-porphyric subjects. In a sample of 82 epileptic patients treated with phenobarbital (n = 54), phenytoin (n = 64), carbamazepine (n = 33), and valproate (n = 8), the daily doses were expressed according to a drug score that would reflect the capacity of these drugs as enzymatic inducers when administered in polytherapy. A significantly increased urinary excretion of D-glucaric acid (DGA) and porphyrins was found in this group of patients (P<0.001), with coproporphyrin being the major fraction in all cases (>60%). Urinary DGA had a highly significant correlation with the drug score (r = 0.783, P<0.001); however, no significant correlations were found between the urinary porphyrins and DGA (r = 0.005) or the drug score (r = 0.053). Neither was any significant relationship found between the urinary porphyrins and the serum activity of 5'-nucleotidase (r = 0.066) or the presence of a cholestasis objectivized through the presence of the isoform of gamma-glutamyltransferase with beta-globulins electrophoretic mobility. However, in a group of 10 patients a significant correlation was found between the urinary excretion of porphyrins and beta-N-acetylhexosaminidase (r = 0.790, P<0.01). Therefore, it does not appear that the liver enzyme induction, or even a subclinical cholestasis, produced by the antiepileptic drugs administered to these patients may serve to explain the increase in the urinary excretion of porphyrins. A possible renal origin is proposed for the increase of urinary porphyrins in these cases.

Adult↗
PubMed2001

Bile acid metabolism by fresh human colonic contents: a comparison of caecal versus faecal samples.

BACKGROUND: Deoxycholic acid (DCA), implicated in the pathogenesis of gall stones and colorectal cancer, is mainly formed by bacterial deconjugation (cholylglycine hydrolase (CGH)) and 7 alpha-dehydroxylation (7 alpha-dehydroxylase (7 alpha-DH)) of conjugated cholic acid (CA) in the caecum/proximal colon. Despite this, most previous studies of CGH and 7 alpha-DH have been in faeces rather than in caecal contents. In bacteria, CA increases 7 alpha-DH activity by substrate-enzyme induction but little is known about CA concentrations or CA/7 alpha-DH induction in the human colon. AIMS AND METHODS: Therefore, in fresh "faeces", and in caecal aspirates obtained during colonoscopy from 20 patients, we: (i) compared the activities of CGH and 7 alpha-DH, (ii) measured 7 alpha-DH in patients with "low" and "high" percentages of DCA in fasting serum (less than and greater than the median), (iii) studied CA concentrations in the right and left halves of the colon, and examined the relationships between (iv) 7 alpha-DH activity and CA concentration in caecal samples (evidence of substrate-enzyme induction), and (v) 7 alpha-DH and per cent DCA in serum. RESULTS: Although mean CGH activity in the proximal colon (18.3 (SEM 4.40) x10(-2) U/mg protein) was comparable with that in "faeces" (16.0 (4.10) x10(- 2) U/mg protein), mean 7 alpha-DH in the caecum (8.54 (1.08) x10(-4) U/mg protein) was higher (p<0.05) than that in the left colon (5.72 (0.85) x10(-4) U/mg protein). At both sites, 7 alpha-DH was significantly greater in the "high" than in the "low" serum DCA subgroups. CA concentrations in the right colon (0.94 (0.08) micromol/ml) were higher than those in the left (0.09 (0.03) micromol/ml; p<0.001) while in the caecum (but not in the faeces) there was a weak (r=0.58) but significant (p<0.005) linear relationship between 7 alpha-DH and CA concentration. At both sites, 7 alpha-DH was linearly related (p<0.005) to per cent DCA in serum. INTERPRETATION/SUMMARY: These results: (i) confirm that there are marked regional differences in bile acid metabolism between the right and left halves of the colon, (ii) suggest that caecal and faecal 7 alpha-DH influence per cent DCA in serum (and, by inference, in bile), and (iii) show that the substrate CA induces the enzyme 7 alpha-DH in the caecum.

Aged↗
PubMed1970

Induction of glutamine synthetase in embryonic retina: its dependence on cell interactions.

A relation between enzyme induction in embryonic cells and cellular organization is indicated by the finding that the levels of glutamine synthetase induced by hydrocortisone in the embryonic neural retina in vitro are dependent on the associations between the retina cells. Intact retina tissue, aggregates of dissociated cells, and cells in monolayer culture showed a decreasing response, in this order, to glutamine synthetase induction. With time of culture, the enzyme activity continued to rise in the intact retina and in cell aggregates, but activity declined in monolayer cultures even though the inducer was continuously present. Dispersed cells cultured in monolayer without the inducer showed after 24 hours a loss of inducibility which could not be reversed by reaggregating such modified cells but could be prevented by maintaining the freshly dispersed cells at a low temperature.

Animals↗
PubMed1990

Increased hepatic nicotine elimination after phenobarbital induction in the conscious rat.

Elimination parameters of [14C]nicotine in conscious rats receiving nicotine (0.3 mg/kg) either intravenously or orally were studied. The oral availability of unchanged nicotine, derived by comparison of the respective areas under the concentration vs time curves (AUC), was 89%, indicating low hepatic extraction ratios of about 10%. Pretreatment of rats with phenobarbital (PB) markedly increased hepatic first-pass extraction of nicotine. The oral availability of unchanged nicotine in plasma dropped to 1.4% of the corresponding values obtained from PB-treated rats receiving nicotine iv. After PB pretreatment, the clearance of iv nicotine was increased approximately twofold over controls, much less than the observed more than ninefold increase of hepatic first-pass extraction. It is assumed that extrahepatic metabolism contributed significantly to the rapid removal of nicotine from the plasma. The elimination of cotinine, originating from nicotine administered either po or iv, was significantly increased by PB pretreatment, as determined by the ratio of corresponding AUCs. The pattern of nicotine metabolites in urine also indicated an increase in the rate of cotinine metabolic turnover. The amount of norcotinine in the organic extract of urine paralleled PB microsomal enzyme induction. The ratio between urinary concentrations of the normetabolite and cotinine correlated strongly with the PB-induced state of rat liver. This may be a suitable indicator of PB-inducible hepatic cytochrome P450 isoenzyme(s). Since smoking habits in man are feedback-regulated by nicotine plasma concentrations, a similar increase of nicotine elimination by microsomal enzyme induction in man may be of relevance for tobacco consumption.

Administration, Oral↗