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PubMed1995

The influence of rifampin treatment on caffeine clearance in healthy man.

BACKGROUND/AIMS: Since cytochrome P450IA2 is involved in the metabolism of procarcinogens and carcinogens, there is debate about whether induction of this enzyme system by pharmaceuticals leads to a higher risk of malignancy. We investigated rifampin as a potent inducer of the hepatic mixed function oxygenase system and its effect on caffeine metabolism which can be taken as an in vivo marker of cytochrome P450IA2 activity. METHODS: Caffeine clearance was measured in ten healthy volunteers before and after a 7-day treatment with 600 mg rifampin. Urinary 6 beta-hydroxycortisol output was used as endogenous marker of microsomal enzyme function. RESULTS: 6 beta-hydroxycortisol increased from 7.6 to 26.0 micrograms/24 h per kg after treatment with rifampin, consistent with the induction of mixed function oxidases in the liver. There were significant changes in caffeine plasma half-life (6.2 vs. 3.5 h; p < 0.004) and caffeine plasma clearance (1.3 vs. 2.2 ml/kg per min; p < 0.004) with rifampin. CONCLUSIONS: The hypothesis that induction of cytochrome P450IA2 entails accelerated activation of procarcinogens would predict rifampin to be associated with a higher risk of malignancy. As with other inducers of cytochrome P450IA2, such as phenytoin or omeprazole, no such linkage is known. Therefore the role of pharmaceutical induction of cytochrome P450IA2 in tumor promotion remains unclear.

Caffeine↗
PubMed1998

In vitro immunosuppressive activity, isolation from pig liver microsomes and identification by electrospray ms-ms of a new FK-506 C19-C20 epoxide metabolite.

In order to mediate their effects, cyclosporin A and FK-506 must each bind with high affinity to a cytosolic target protein that belongs to the immunophilin group. FK-506 forms complexes with the FK-506 binding protein FKBP, mainly FKBP-12, and these complexes possess immunosuppressive activity through their ability to interact with another target, the abundant serine threonine phosphatase calcineurin. Evaluating the immunosuppressive activities of the FK-506 metabolites by comparing them with known immunosuppressive agents via mixed lymphocyte reaction is of clinical importance because some metabolites may retain the pharmacological activity of the parent drug or exhibit cytotoxic effects. FK-506 is metabolized by the cytochrome P-450-dependent mixed-function oxygenase system in different animal species, and we are reporting the isolation from pig liver microsomes, and the identification by electrospray ms-ms, of the FK-506 C19-C20 epoxide metabolite. We found that this new metabolite exhibits reduced in vitro immunosuppressive activity compared with FK-506 and has approximately the same immunosuppressive potency as other known immunosuppressive drugs, such as cyclosporin A and IMM-125, a hydroxyethyl derivative of D-serine cyclosporin A. We were able to demonstrate that after incubation of the FK-506 metabolite in human mixed lymphocyte reaction cultures for 6 days, the compound was stable under the conditions used for cell culture as evidenced by electrospray-ms data. A weak direct cytotoxic effect (< 30% cell death) was observed only at the highest concentrations (2500 and 5000 ng/ml), which shows that the mixed lymphocyte reaction inhibition cannot be due to a toxic effect.

Animals↗
PubMed1975

In vitro metabolic conversion of aflatoxins and benzo(alpha)pyrene to nucleic acid-binding metabolites.

An aflatoxin B1 metabolite was found to become covalently bound to rat liver RNA and calf thymus DNA in vitro, and it formed complexes with increased spectral absorbance in the 360 nm region. The formation of such complexes was reduced nicotinamide adenine dinucleotide phosphate and microsome dependent, was inhibited by theta-diethylaminoethyl diphenylpropylacetate-HC1, and by CO and N2, when the latter were used to replace the gas phase of the incubations. The formation of the complexes was enhanced about 2-fold with cicrosomes from phenobarbital-treated rats but not from 3-methylcholanthrene-treated rats. More binding was observed with DNA than RNA. Dentured DNA was about 70% as effective as native DNA. Nucleic acids from various sources showed the following order of binding potency: DNA from Micrococcus luteus greater than DNA from calf thymus equal to DNA from rat liver greater than RNA from rat liver greater than transfer RNA from rat liver. In the presence of reduced nicotinamide adenine dinucleotide phosphate and microsomes from phenobarbital-treated rats, aflatoxin G1 was also converted into metabolite(s) that became covalently bound to nucleic acids and formed complexes with increased spectral absorbances in the 360 nm region: this reaction was also inhibited by theta-diethylaminoethyl diphenylpropylacetate-HC1. Under the same conditions, aflatoxin B2, aflatoxin G2, aflatoxin B2a, and "Compound 11," which lack a C2-C3 double bond, did not show any noticeable binding to either DNA or RNA. These data strongly support the concept that the microsomal mixed-funciton oxygenase-catalyzed oxidation of the C2-C3 double bond of aflatoxins is a prerequisite for the formation of nucleic acid-binding metabolites. Microsomes from untreated, phenobarbital-treated, and 3-methylcholanthrene-treated rats were compared in vitro for their ability to catalyze the formation of DNA-binding metabolites from aflatozin B1 and benzo(a)pyrene. In assays involving benzo(a)pyrene, microsomes from 3-methylcholanthrene-treated rats were 12- and 5-fold more active than microsomes from untreated and phenobar-bital-treated rats, respectively. This is in contrast to the results obtained with aflatoxin B1 and suggests that different enzymes in the hepatic microsomal mixed-function oxygenase complex are involved in the generation of reactive metabolites from various polycyclic hydrocarbons.

Aflatoxins↗
PubMed1979

The structure-activity relationships of halogenated biphenyls as enzyme inducers.

Polyhalogenated biphenyls induce microsomal mixed-function oxygenases in many species including man. They can be divided into two classes of inducers. 3,4,5,3',4', 5'-Hexa- and 3,4,3',4'-tetrachlorobiphenyls appear to interact with the TCDD receptor, albeit at 100 to 1,000 times the dose. The structure required for 3-MC (TCDD)-type induction seems to be the presence of at least two adjacent halogens in the lateral positions (meta and para) of the benzene rings, and an absence of halogens in the ortho positions adjacent to the biphenyl bridge. It is likely that halogenation of the ortho positions prevents binding by blocking planar configuration. These isomers, although less toxic than TCDD, are much more toxic than other PCB isomers. Most halogenated biphenyl isomers are phenobarbital type inducers or are inactive. The structure-activity relationship for this type of induction is less clear, but active isomers include 2,4,2',4'-tetra-; 2,4,5,2',4',5'-; 2,3,4,2',3',4'-; 2,3,5,2',3'.5'-and 2,4,6,2',4',6'-hexachlorobiphenyls and 2,4,5,2',4',5'-hexabromobiphenyl. The inactivity of many of the lower chlorinated isomers as inducers (mono-through tetrachloro-) may be related to their rapid metabolism. The cytochrome which is induced by commercial PCB and PBB mixtures appears to be identical to a mixture of cytochromes from phenobarbital- and 3-MC-treated rats. These structure-activity relationships suggest that the "mixed inductive" effects and much of the toxicity of PCB and PBB mixtures are due to the presence of compounds related structurally to the active chlorinated dibenzofurans or 3,4,3',4'-tetrachlorobiphenyl.

Animals↗
PubMed1999

Liver microsomal cytochromes P450-dependent alkoxyphenoxazone O-dealkylation in vitro by alligator and rat: activities, inhibition, substrate preference, and discrimination factors.

Six substituted alkoxyphenoxazones (resorufins) and four inhibitors of P450-dependent mixed-function oxygenases (MFO) were used to probe the breadth and extent of P450 metabolism induced by pretreatment with five xenobiotic chemicals in liver microsomes of the American alligator, Alligator mississippiensis. Phenobarbital (PB), 3-methylcholanthrene (3MC), and PB-3MC co-pretreatment elicited major induction of alligator MFO activity measured by alkoxyresorufin O-dealkylation (AROD). The induced levels of activities observed with appropriate substrate, 7-ethoxy, 7-methoxy, 2-phenylbenzyloxy, 7-pentoxy, or 7-benzyloxyresorufin (EROD, MROD, PBROD, PROD and BROD, respectively), were 10 to 100 times lower in alligator as compared to rat. The exception was a higher level of isopropoxyresorufin O-dealkylation (IPROD) in alligator. The induction regimes used in alligator and rat revealed marked differences in substrate preference, discrimination factors (DF) for various inducible P450 isoforms. EROD, a classic indicator of CYP1A activity in rat, had a low DF in alligator. MROD was the best discriminator in alligator of CYP1A-type induction. In contrast to rats, pretreatment of alligators with Aroclor 1254, 2,2',4,4' tetrachlorobiphenyl, and clofibrate caused minor alterations in AROD relative to untreated controls. The inhibitors, alpha-napthaflavone, 1-ethynylpyrene, SKF 525A, and 9-ethynylphenanthrene, inhibited AROD activity of the expected P450 isoform. For example, 10 microM alpha-napthaflavone inhibited liver microsomal EROD catalyzed by 3MC-inducible isoforms from alligator by 90% and from rat by 97%. Similarly, 10 microM SKF 525A inhibited PROD catalyzed by PB-inducible isoforms by 63% and 79% in alligator and rat liver microsomes, respectively. To the best of our knowledge, the present studies are the first to show PB induction of P450 activities typical of the mammalian CYP2 family and their inhibition with classical inhibitors in alligator liver. While our data indicate metabolism of P450 substrates with preferences to certain isoforms, it remains to be established which isoforms exert catalytic function in alligator and whether these are homologues or orthologues of mammalian isoforms.

Alligators and Crocodiles↗
PubMed1990

Effect of nifedipine on antipyrine and theophylline disposition.

On the basis of reports that some calcium channel blockers impair the elimination of some drugs, the effect of nifedipine on the disposition of antipyrine and theophylline was assessed in healthy volunteers. Antipyrine half-life of 10.04 +/- 1.43 h (mean +/- SD) after a week intake of nifedipine (20 mg twice daily) was not significantly different from the control value of 10.64 +/- 2.15 h; nor was that of 10.02 +/- 1.49 h after 2 weeks pretreatment with the calcium channel blocker in eight healthy volunteers. Control antipyrine clearance (ml min-1) of 44.40 +/- 10.58 was not significantly different from that of 45.66 +/- 9.34 and 46.87 +/- 9.63 after nifedipine pretreatment of 1 and 2 weeks, respectively. Similarly volume of distribution was unaltered: 0.601 +/- 0.074, 0.591 +/- 0.078 and 0.602 +/- 0.051 l kg-1, respectively. A week pretreatment with nifedipine did not significantly alter either of theophylline half-life (7.32 +/- 0.81 h (control) to 7.50 +/- 0.80 h) or clearance (42.10 +/- 5.84 ml min-1 (control) to 43.77 +/- 4.00 ml min-1) in six volunteers. However the change in volume of distribution: 0.451 +/- 0.053 l kg-1 (control) to 0.483 +/- 0.062 l kg-1 was significant (p less than 0.025). Generally, theophylline plasma levels were lower after nifedipine pretreatment and the difference was significant at 2 and 4 h post-dosing (p less than 0.05). It is suggested that nifedipine, unlike diltiazem and verapamil, is unlikely to interfere with the functional integrity of the hepatic mixed-function oxygenase enzymes, but might displace theophylline from plasma protein.

Adult↗
PubMedDate not supplied

Metabolism of bumetanide.

The metabolism of bumetanide is reviewed, with emphasis on the relationship between metabolism and diuretic activity. Substantial evidence has been obtained for the thesis that diuretic activity is dependent on the amount of bumetanide which reaches the renal tubule. Therefore, bumetanide is a potent diuretic in those species, e.g., human and dog, in which a substantial fraction of the administered dose is excreted as unchanged drug in the urine. In contrast, relatively weak diuretic activity is seen in the rat, a species which very effectively biotransforms bumetanide to inactive metabolites. The metabolites which have been identified in human and rat urine are presented, and the point is made that in both species metabolism of bumetanide appears to be limited to oxidation of the N-butyl side chain. Different (and unidentified) metabolites are excreted by the dog. A prominent metabolite formed in the dog, however, is the acylglucuronide of bumetanide, which was detected in plasma and bile but was not seen in urine or feces. Tissue distribution of bumetanide in the dog is presented so as to show the ability of the kidney to concentrate bumetanide. In the human, bumetanide disposition is also characterized by 95 per cent plasma protein binding and a plasma half-life of 1 to 2 hours. Attention is given to the possibility that the clinical response to bumetanide can be altered by factors which affect drug oxidation by the mixed-function oxygenase system; e.g., induction of the drug-metabolizing enzymes may lead to increased biotransformation of bumetanide and concomitant decreased diuretic activity.

Animals↗
PubMed1985

The hepatotoxicity of carbon disulphide in sheep.

Carbon Disulphide (CS2) caused liver injury when dosed orally (intraruminally) at 0.05 ml per kg body weight to overnight fasted sheep which had been given 200 mg kg-1 DDT intraruminally 1 week previously to enhance the hepatic mixed function oxygenases. The liver lesion was a periacinar hepatocellular vacuolar degeneration, fully developed at 24 h and lasting from 4 to 5 days after which the hepatic morphology returned to normal. At 24 h after dosing with CS2 there was an increase in total liver water, sodium and potassium ions but without an increase in the concentration of these cations in total liver water, and a 50% reduction in microsomal cytochrome P450 levels. Calcium concentration was either unchanged or only slightly increased. The cytoplasmic vacuoles were mainly distensions of the rough endoplasmic reticulum and contained fine amorphous or fibrillary material, probably originating from damaged smooth endoplasmic reticulum membranes. The transient influx of fluid into these organelles is thought to be due to osmotic action generated by molecules derived from the latter macromolecular membrane fragments. The lesion resembles that seen in the rat due to CS2 after pretreatment with phenobarbitone. In situations in which sheep are drenched with CS2 and CCl4 in combination, it is suggested that the development of hepatic periacinar hydropic change due to the CS2 in animals normally susceptible to CCl4 because of enhanced microsomal cytochrome P450 levels would provide a better chance of survival than if CCl4 alone was administered and extensive periacinar coagulative necrosis occurred.

Animals↗
PubMed2005

Interseasonal variability in biomarkers of exposure in fish inhabiting a southwestern Australian estuary.

The Swan-Canning Estuary, in southwestern Australia, undergoes distinct seasonal changes, with freshwater discharge predominant in the winter (wet) season and low flow with high salinity predominant in the dry summer season. To investigate seasonal variability in biomarkers of exposure in fish, black bream (Acanthopagrus butcheri) were collected from seven sites in the Swan-Canning Estuary in winter 2000 and in summer 2001. No interseasonal or intersite differences in serum sorbitol dehydrogenase concentration were found, indicating the measured mixed-function oxygenase (MFO) enzymes were not influenced by liver damage. The ethoxyresorufin-O-deethlyase (EROD) activity of the postspawning females was higher in summer than in winter but was significantly lower than that in males in both seasons, suggesting estradiol suppression in females. Sexual differences in ethoxycoumarin-O-deethylase (ECOD) activity were not evident in either season. Both EROD and ECOD activities and polycyclic aromatic hydrocarbons (PAH) biliary metabolites had significantly different patterns of induction between seasons. The ratio of naphthalene-type to benzo(a)pyrene-type biliary metabolites was significantly higher in summer, indicating the sources of petroleum hydrocarbons were petrogenic compared to in winter, when the source was a mixture of pyrogenic and petrogenic PAHs. There was no upstream or downstream gradient of response in any biomarker in either season, demonstrating that there were multiple sources of contaminant input into the estuary. Although winter biomarker levels were triggered by the discharge runoff from major roads and drains, summer biomarker levels appear to have been related to recreational boating use on the estuary.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1995

Suitability of the ruffe (Gymnocephalus cernua [L.]) for investigations on activity of hepatic enzymes induced by xenobiotics.

Activity measurements of enzymes catalyzing (i) the oxidation of xenobiotics (phase I) and (ii) the conjugation of metabolites produced in phase I (phase II) were carried out in ruffe to test its suitability for biological monitoring. Ruffe typically lives in the lower regions of rivers and in estuaries where monitoring is of particular interest for estimating the amount of pollutants introduced into the sea. The flounder, already examined for this purpose, is used as reference organism. In ruffe, the enzymatic activity (7-ethoxycoumarin-O-deethylase (ECOD) and 7-ethoxyresorufin-O-deethylase (EROD)) increased with the contamination of the river toward Hamburg whereas in flounder it did not. The absence of a correlation between induction of the enzymatic activity in flounder and environmental contamination is attributed to the higher readiness of the flounder to migrate. Therefore, mixed function oxygenase activity found in flounders may not represent the inducing capacity of the local concentrations of xenobiotics. Since ECOD activity in ruffe was 5 to 20 times higher compared to the flounder, histopathological findings of investigations of the liver tissue were considered. Destruction or pathological changes of the endoplasmatic reticulum (where ECOD and EROD are located) is often reported in flounder but not in the ruffe, which may influence the expression of some enzymatic activities. The enzymatic activity of the phase II enzyme glutatione-S-transferase, which is considered to have a protective function in the cell against damages, caused by reactive metabolites, was more induced in ruffe than in flounder. Thus the ruffe may be less subjected to cell injury.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Acute cytotoxicities of polynuclear aromatic hydrocarbons determined in vitro with the human liver tumor cell line, HepG2.

The neutral red in vitro cytotoxicity assay was adapted for use with the human hepatocellular tumor cell line HepG2 to detect the cytotoxic potencies of polynuclear aromatic hydrocarbons (PAHs). Using benzo[a]pyrene (B[a]P) as the representative PAH, it was determined that a 3-day exposure was the most suitable for detecting cytotoxic potency and that preexposure to 5 micrograms/ml Arochlor enhanced the sensitivity of the HepG2 cells to the toxicant. Such enhanced sensitivity probably reflected increased metabolic conversion of the B[a]P to active metabolites after culturing the cells in the presence of Arochlor. This was shown by a 3-fold increase in the activity of 7-ethoxycoumarin deethylase, an indicator of mixed-function oxygenase activity. Furthermore, a reduction in sensitivity to B[a]P occurred when the cells were cultured in the presence of alpha-napthoflavone, an inhibitor of aryl hydrocarbon hydroxylase activity. When Arochlor-induced cells were transferred to medium lacking Arochlor, the level of 7-ethoxycoumarin deethylase quickly declined to basal levels. Arochlor-induced cells were also able to detect the cytotoxic potencies of benzo[k]fluoranthene, benzo[b]-fluoranthene, chrysene, benzo[a]anthracene pyrene, phenanthrene, and fluoranthene, whereas fluorene, anthracene, acenaphthene, and acenaphthylene were not cytotoxic.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

Pharmacokinetics and endocrine effects of terguride in healthy subjects.

Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i.v. dose of 50 micrograms and on the first and seventh day of an oral treatment with 250 micrograms, 500 micrograms and 750 micrograms b.d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH)-stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA. Following the i.v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml.min-1.kg-1. The oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6 beta-OH cortisol.

Adult↗
PubMed1975

Metabolism of trichloroethylene in man. III. Interaction of trichloroethylene and ethanol.

Volunteers inhaled a constant concentration of 50 ppm trichloroethylene (Tri) for 6 hrs per day on 5 consecutive days. Simultaneous ethanol (EtOH) ingestion (blood level 0.6%) inhibits the metabolization of Tri to trichloroethanol (TCE) and trichloroacetic acid (TCA) by 40% on the average. Oxidation of Tri to TCA does not occur as long as EtOH is present. During this time period the blood Tri-concentration increases 2 1/2-fold, that in the expired air rising 4-fold, as compared to Tri inhalation without EtOH. TCE glucuronidation is not subject to inhibition. On concurrent inhalation of Tri, the EtOH and acetaldehyde levels are slightly increased over the control values without Tri. The mechanisms underlying the alternate inhibition of mixed-function oxygenases and aldehyde dehydrogenase on simultaneous intake of Tri and EtOH are discussed. The intolerance reaction occurring on combined exposure to Tri and EtOH can be interpreted as an accumulation of Tri in the CNS resulting from the complete depression of Tri oxidation.

Acetaldehyde↗
PubMed1976

Aryl hydrocarbon hydroxylase and 16alpha-hydroxylase in cultured human lymphocytes.

Aryl hydrocarbon hydroxylase and 16alpha-hydroxylase were examined in intact, cultured human lymphocytes. The two microsomal mixed-function oxygenases had different pH optima and showed competitive inhibition for enzyme induction and activity. Population distributions were lognormal for both enzymes, giving apparent evidence for polygenic control. Induced levels of AHH were slightly higher among first-order relatives of lung or colon cancer patients than in the control group. The correlation coefficient (r) for AHH and SAH coinducibility was -0.08, indicating no correlation and suggesting the absence of association between the two enzymes in man.

Aryl Hydrocarbon Hydroxylases↗
PubMed1991

The induction of cytochrome P-450-IA1 in juvenile fish by creosote-contaminated sediment.

Intact sediment cores, including their surface layers, were used in simulated field exposure tests of juvenile guppies (Poecilia reticulata) to creosote-contaminated sediments. Mixed-function oxygenase activity was induced in the fish after 43 days of exposure to environmentally realistic, sublethal concentrations of creosote-related compounds. An average 50-fold induction in the cytochrome P-450-IA1 was found in the liver in the absence of any histopathological lesions. The possibility that a threshold level for proliferative liver changes was not reached is discussed in the light of the observed biochemical activation.

Animals↗
PubMed2002

Polycyclic aromatic hydrocarbon metabolites in the bile of a territorial benthic fish, oyster toadfish (Opsanus tau) from the Elizabeth River, Virginia.

Reverse-phase high-performance liquid chromatographic analyses of bile of a territorial benthic fish, oyster toadfish (Opsanus tau), indicated that fish from reference stations in the York and Elizabeth Rivers, Virginia, contained lower concentrations of polycyclic aromatic hydrocarbon (PAH) metabolites than fish from polluted stations. PAH metabolite levels in the bile of fish from mildly polluted stations were 7 to 10 times greater than those from reference stations. PAH metabolite levels in fish from a moderately polluted station and a highly polluted station were, respectively, 20 and 50 times greater than those from reference stations. Differential patterns of five major PAH metabolites in fish from the same station suggested individual variability in metabolic pathways possibly further convoluted by the differential inductions or suppressions of hepatic mixed-function oxygenase isozyme systems under various natural or anthropogenic habitat parameters. PAH metabolite levels in the bile of oyster toadfish correlated well with the gradient of PAH contamination in the Elizabeth River sediments. High levels of biliary PAH metabolites were not detected in muskrats (Ondatra zibethicus) collected along the polluted sections of the Elizabeth River, probably due to their primarily herbivorous nature. Assuming that the hepatobiliary system and the gastrointestinal tract are the major routes of biotransformation and excretion of PAHs in the muskrats, the contaminated diet appears to be a more important routes of exposure of muskrats (and possibly oyster toadfish) to PAHs than the transdermal transfer. Occurrence permitting, we propose oyster toadfish as a useful biological sentinel for early detection of estuarine PAH pollution.

Adaptation, Physiological↗
PubMed1976

Modifications of drug metabolism by disulfiram and diethyldithiocarbamate. II. D-Glucuronic acid pathway.

Hepatic enzymes connected with the formation and metabolism of free D-glucuronic acid were affected in rats after treatment with disulfiram or diethyldithiocarbamate (300 mg/kg, intragastrically, per day, 4 X). The activities of UDPglucose dehydrogenase, UDPglucuronic acid pyrophosphatase, UDPglucuronosyltransferase and L-gulonate dehydrogenase were enhanced, while those of glucose-6-phosphate dehydrogenase, beta-glucuronidase and D-glucuronolactone dehydrogenase were inhibited. These changes were more pronounced with disulfiram than diethyldithiocarbamate. Treatment with phenobarbital (80 mg/kg, i.p., per day, 4 X) enhanced UDP glucuronosyl-transferase, but brought about different effects on the other enzymes. Concurrent administration of phenobarbital with disulfiram or diethyldithiocarbamate led to potentiation or antagonism of the primary effects of each compound when given alone. The results suggest that activation of the D-glucuronic acid pathway may proceed in various ways, and that it is not necessarily followed by a simultaneous induction of the microsomal mixed-function oxygenase activity.

Alcohol Oxidoreductases↗