Expression of multi-drug resistance genes (mdr1, mrp1, bcrp) in primary oral squamous cell carcinoma.

UNLABELLED: The expression of resistance genes can cause the ineffectiveness of chemotherapeutics for the treatment of cancer. Therefore, known resistance genes were investigated in oral squamous cell carcinoma (OSCC) and the results were compared with clinico-pathological findings. MATERIALS AND METHODS: Fresh frozen samples of 45 primary OSCC were investigated for the expression of mdr1 (p-glycoprotein-mediated multi-drug resistance), mrp1 (multi-drug resistance-related protein) and bcrp (breast cancer-related protein), using a reverse transcriptase PCR. The gene products were revealed immunohistochemically on representative slices of the same tumor sample. The results were compared with TNM stage grouping [SG, (UICC, 1987)], HPV infection and p53 mutations (exons 5-8). RESULTS: The expression of the resistance genes was independent of age, sex, localisation of the tumor, HPV infection and p53 mutations. SG did not correlate to mdr1 and mrp1. On the other hand, bcrp expression increased 2.7-fold between SG III and IV OSCC. Loss of differentiation was associated with an increased expression of mdr1 (p=0.06), mrp1 (p<0.01) and bcrp (p<0.01). The bcrp expression correlated with shorter survival periods. Expression of mrp1 and mdr1 did not correlate positively in a linear pattern. Expression of mdr1 and bcrp moderately positively correlated (p<0.01). DISCUSSION: Multi-drug resistance genes can be up-regulated in OSCC. The expression of at least one of these genes is up-regulated in SG-IV OSCC. Determining these genes could probably support current studies on therapeutic effects in OSCC, e.g. new cytostatic drugs.

Effects of pravastatin on cholesterol metabolism of cholesterol-fed heterozygous WHHL rabbits.

1. We administered the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin at a daily dose of 1 mg kg(-1) body weight to cholesterol-fed (0.03%) heterozygous Watanabe heritable hyperlipidaemic rabbits, an animal model for heterozygous familial hypercholesterolaemia. 2. After 12 months of cholesterol treatment, immunohistochemistry with the monoclonal antibody 9D9 was used to detect hepatic low density lipoprotein (LDL) receptors, which were quantified by densitometry. In addition we determined LDL receptor mRNA by competitive reverse transcriptase polymerase chain reaction. The cholesterol precursor lathosterol and the plant sterol campesterol were analysed by gas-liquid chromatography. 3. The drug reduced total plasma cholesterol levels by 51% (P=0.04), when compared to the control group. Unexpectedly, hepatic LDL receptor density and mRNA showed no significant differences between the groups. Total plasma levels of lathosterol and campesterol also revealed no significant differences between the groups, if expressed relative to plasma cholesterol. 4. The findings suggest that mechanisms other than induced hepatic LDL receptors are responsible for the cholesterol-lowering effect of pravastatin in this animal model. We propose a reduced cholesterol absorption efficiency compatible with similar campesterol levels between both groups observed in our study.

No evidence of significant activity of the multidrug resistance gene product in primary human breast cancer.

BACKGROUND: The discovery of the multidrug resistance (MDR1) gene product P-glycoprotein (P-gp) has been widely seen as an important milestone in our understanding of the mechanisms underlying the clinical phenomenon of the emergence of resistant cells. MDR1 expression has been shown for numerous solid tumors and for virtually all hematologic malignancies. Nevertheless, results regarding MDR1/P-gp expression in human breast cancer have been controversial and the results of clinical trials on modulation of P-gp activity have not been encouraging. PATIENTS AND METHODS: MDR1/P-gp expression and the function of the P-gp pump were investigated in 61 tumor samples from patients with primary breast cancers by multiparameter analysis using MDR1-RT-PCR, immunohistochemistry with two MAbs (UIC2 and MRK16) and the rhodamine 123 (Rh123) efflux assay. The cellular composition of the tumor cell suspension was analyzed by using specific MAbs against the P-gp expressing lymphocyte subsets CD4, CD8 and CD56, as well as against the HER-2/neu gene product, which was used to identify breast carcinoma cells. RESULTS: UIC2 and MRK16 revealed a staining positivity in 72% and 75% of samples, respectively. A positive MDR1-RT-PCR signal was detected in 62% of the samples. Nevertheless, no correlation between immunohistochemistry and RT-PCR could be established. Furthermore, there was no correlation between HER-2/neu expression and MDR1-RT-PCR or P-gp immunohistochemical assays. A contamination by CD8+ and CD4+ lymphocytes was established in 100% and 84% of tumor cell suspensions, respectively. As assessed by the Rh123 efflux assay CD8+ and the CD4+ lymphocytes exhibited marked P-glycoprotein activity, whereas such activity was not detectable in a single instance for the breast carcinoma cells. In MDR1-RT-PCR positive samples, contamination by CD8 lymphocytes averaged 4.3%, while the contamination of CDS cells in the MDR1 mRNA-negative samples was only 2.4% (P = 0.007). This signal vanished after elimination of the lymphocyte subpopulations by T-cell rosetting. CONCLUSIONS: In primary breast cancer detection of MDR1 gene expression by means of RT-PCR or immunohistochemical assays is not indicative for the MDR phenotype, since there is no evidence of significant activity of the P-gp pump.

Expression of the novel mitoxantrone resistance associated gene MXR7 in colorectal malignancies.

It was shown previously that a glypican encoding gene (MXR7/GPC3/OCl-5) was associated with mitoxantrone resistance in vitro. This study describes and investigation of an association between multidrug resistance and MXR7 in surgical cryo-specimens of 51 gastrointestinal tumors. The mRNA expression levels differ widely according to tumor species. In primary colorectal cancers, the level of MXR7 mRNA expression correlated loosely with the mRNA expression level of the multidrug-resistance-associated protein (MRP). In colorectal metastases an elevated MXR7 mRNkA expression level was observed when compared to primary colorectal carcinomas.

[Morphological and functional features of cytostatic drug resistance and the effects of MDR modulators]. / Morphologische und funktionelle Befunde zur Zytostatika-Resistenz und der Wirksamkeit von MDR-Modulatoren.

Manifold mechanisms of resistance can be expressed by malignancies. Profound information on this aspect is a prerequisite for comprehensive individual chemotherapy. Based on both morphological and functional findings, the diagnosis of P-Glycoprotein (P-Gp) mediated Multidrug Resistance (MDR) can be verified. In order to describe minimum criteria for conclusive diagnosis, morphological and biochemical findings (Immunocytochemistry, RT-PCR, ultrastructural and Laser-Scan microscopy) and functional data (cytostatic drug transport, proliferation) were correlated in tumor cell lines of the MDR phenotype as opposed to cells with atypical resistance. Frequently, single features of MDR are found in atypical, P-Gp negative resistance. Accumulation deficits for mitoxantrone based on vesicular drug transport were found in P-Gp negative gastric carcinoma cell line EPG85-257RNOV. Nocodazole blocked microtubule formation which is essential for vesicle transfer from perinuclear regions to the periphery of the cytosol. Cytochalasin blocked exocytosis of drug containing vesicles. MDR modulators were ineffective. Alternatively, P-Gp mediated drug extrusion and exocytosis of drug containing vesicles may constitute complementary mechanisms of resistance. In gastric carcinoma cells EPG85-257DAU, MDR modulators do increase cytosolic daunorubicin load, but drug binding to nuclear target sites is still inhibited due to drug containment within vesicles. To complicate matters, MDR modulators may be functional even in MDR negative cells, as shown in a panel of melanoma cell lines. Data show that conclusive diagnosis of P-Gp-mediated MDR should be based on more than one experimental approach including immunocytochemistry, a sensitive assay such as RT-PCR and--whenever feasible--a functional test.

In vivo reversibility of multidrug resistance by the MDR-modulator dexniguldipine (niguldipine derivative B859-35) and by verapamil.

The newly synthesized dihydropyridine derivative B859-35 was previously shown in vitro to be highly effective in reversing multidrug resistance (MDR) of P-glycoprotein positive tumor cell lines, such as the adriamycin (ADR) resistant erythroleukemia F4-6RADR cells. In the current study B859-35 was investigated for its efficiency in reversing MDR in an in vivo tumor model for preclinical testing of MDR-modulators. F4-6RADR cells were injected into the right flank of nude mice while the parent cells were injected into the left flank. The animals were treated i.p. with ADR (9.0 mg/kg body weight) combined with B859-35 (5, 10, or 25 mg/kg) or, for comparison and validation, with verapamil (VRP) (75 mg/kg). The effects of ADR and the MDR-modulator combination were evaluated by histological morphometry of the tumors. While ADR alone was shown to be ineffective in resistant cells, the combinations of ADR + B859-35 as well as of ADR + VRP were highly active in reducing the number of viable cells in the resistant tumor nodule by 67 +/- 9% or by 53 +/- 11% of controls. This model provides evidence that even in vivo, MDR modulators can be effective in reversing drug resistance. In addition, it presents a potentially useful and rapid preclinical system for in vivo studies on the modification of drug resistance.

The technique of endobronchial lidocaine administration does not influence plasma concentration profiles and pharmacokinetic parameters in humans.

This study investigated plasma concentration profiles, pharmacokinetic characteristics and side-effects of lidocaine following 3 different administration techniques. Sixty ASA I/II patients undergoing elective ENT-operations were randomised into 4 groups. Lidocaine 1% (1 mg/kg) was administered 50 min before the end of the operation, via a regular endotracheal tube (group 1), a suction-catheter deep endobronchially (group 2), or an EDGAR-(Endobronchial-Drug and Gas Application during Resuscitation)-tube characterized by a separate injection channel ending at the orifice of the tube (group 3). For the control group, a regular endotracheal tube was inserted without lidocaine administration (group 4). Anesthesia was induced with propofol (2 mg/kg), sufentanil (0.5 micrograms/kg), and vecuronium (0.08 mg/kg) and continued as total intravenous anesthesia with propofol (8 mg/kg/h) and oxygen in air (FiO2 = 0.33). A control and 13 blood samples were taken up to 180 min after lidocaine administration. Lidocaine plasma concentrations were determined using a fluorescence polarization immunoassay (TDxFLx). Heart rate, blood pressure, endtidal PcO2, and oxygen saturation were similar in all groups investigated. Ventilation was interrupted for 3.6 +/- 0.5 s in group 1 and 10.2 +/- 0.8 s in group 2, to administer lidocaine. Patients from group 3 were ventilated continuously because of a separate injection channel integrated in the EDGAR-tube. Sore throat was significantly increased in group 2 as compared with groups 1, 3 and 4. Asorption of lidocaine in groups 1-3 resulted in maximal mean plasma concentrations ranging from 0.78 to 0.85 micrograms/ml after 16.9 to 22.4 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Secondary combined resistance to the multidrug-resistance-reversing activity of cyclosporin A in the cell line F4-6RADR-CsA.

Multidrug-resistant tumor cells can be resensitized by combined application of the selecting cytostatic drug and a chemosensitizer, such as cyclosporin A (CsA) or a calcium channel blocker. Since clinical trials on the circumvention of multidrug resistance (MDR) with chemosensitizers report disparate results, we investigated whether tumor cells of the MDR phenotype can develop additional resistance to the cytostatic chemosensitizer combination. Thus, the Adriamycin(ADR)-selected, P-glycoprotein-positive MDR Friend leukemia cell line F4-6RADR was exposed to stepwise increased concentrations of CsA at a constant level of 0.05 microgram/ml ADR. The initial CsA concentration (plus 0.05 microgram/ml ADR) to inhibit cell growth of F4-6RADR cells by 50% (IC50) was 0.04 microgram/ml. By continuous incubation for more than 6 months, the IC50 for CsA (at constant ADR) was elevated to 3.6 micrograms/ml (90-fold), thus generating the variant F4-6RADR-CsA. The F4-6RADR-CsA cells were cross-resistant for cyclosporin H (CsH), a non-immunosuppressive derivative of CsA. As shown by immunocytochemistry as well as by the polymerase chain reaction and by Western blotting including densitometry, P-glycoprotein was preserved in the F4-6RADR-CsA variant and was expressed at a 4-fold higher level than in F4-6RADR cells. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis could detect no new proteins in F4-6RADR-CsA as compared to F4-6RADR. Interestingly, resistance of F4-6RADR-CsA cells remained reversible for the calcium antagonists verapamil and dihydropyridine B859-35 (dexniguldipine-HCl), indicating that CsA and these compounds interfere with the P glycoprotein function by different pharmacodynamic mechanisms. Transport studies with [14C]ADR, performed in the presence and absence of chemosensitizers, confirmed the good correlation of P-glycoprotein function with the pattern of resistance found in proliferation assays. Cellular accumulation of [3H]cyclosporin was reduced to 71% of that of the F4-6 controls in F4-6RADR-CsA cells, but remained at the level of controls in F4-6RADR cells. Results indicate that increased amounts of the P-glycoprotein--besides other, perhaps more important mechanisms that are as yet unknown--partially mediate CsA resistance in F4-6RADR-CsA cells. We have designated this new form of resistance "secondary combined resistance" (SCR). The results suggest that at least some clinical cases of insensitivity to chemosensitizers or of relapse after reversing therapy could be explained by SCR, and that resensitizing treatment of tumor patients should be based on the consideration of several chemosensitizers of different pharmacodynamics.

Reversal of multidrug resistance in Friend leukemia cells by dexniguldipine-HCl.

Dexniguldipine-HCl (DNIG)--a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MDR)--was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR), or mitoxantrone (MITO) in resistant F4-6RADR cells to the very levels observed in drug-sensitive F4-6 precursor cells. In parallel with the increase in DNR content (F4-6RADR, solvent: 303 +/- 27 pmol/mg protein; DNIG (3.3 mumol/l): 1,067 +/- 174 pmol/mg protein; F4-6P, solvent: 948 +/- 110 pmol/mg protein; n = 8-9, SEM), the amount of DNR tightly bound to the acid precipitate pellet obtained from F4-6RADR (i.e., protein, DNA, RNA) increased 3.9-times to the levels observed in sensitive F4-6 cells. The main pyridine metabolite of DNIG displayed similar activity. Concentration-response analysis revealed that DNIG and R,S-verapamil (VER) induced 100% reversal of the DNR accumulation shortage associated with the MDR phenotype but DNIG was 8 times more potent than VER (50% inhibitory concentration (IC50), 0.73 vs 5.4 mumol/l). In keeping with the accumulation assay, DNIG was about 10 times more potent than VER in sensitizing F4-6RADR cells to the cytostatic and cytotoxic effects of DNR in proliferation assays. In conclusion, DNIG is a potent in vitro modulator, improving (a) the accumulation of anthracycline-like cytostatics, (b) drug access to cellular binding sites, and (c) the cytostatic action of DNR in F4-6RADR leukemia cells of the MDR phenotype.

Decreased resistance to N,N-dimethylated anthracyclines in multidrug-resistant Friend erythroleukemia cells.

Doxorubicin-resistant Friend erythroleukemia cells, line F4-6 ADM2R, were selected by exposure of wild-type F4-6 cells to doxorubicin concentrations of up to 1 microgram/ml. In these cells, increased expression of multidrug resistance (MDR) genes was demonstrated by Northern blot analysis. The growth-inhibitory effect of doxorubicin, daunorubicin, N,N-dimethyldoxorubicin, N,N-dimethyldaunorubicin, morpholinodoxorubicin, and pyrromycin was comparatively investigated in resistant and wild-type cells. The doxorubicin-resistant F4-6 cells showed approx. 200-fold resistance to doxorubicin and about 100-fold resistance to daunorubicin with respect to the drug-sensitive counterpart. A dramatic decrease in resistance was observed for the N,N-dimethylated derivatives of doxorubicin and daunorubicin as well as for the N,N-dimethylated natural anthracycline pyrromycin and for morpholinodoxorubicin. Uptake studies using [14C]-daunorubicin and [14C]-N,N-dimethyldaunorubicin in resistant F4-6 cells showed a decreased accumulation of daunorubicin but no significant reduction in N,N-dimethyldaunorubicin accumulation as compared with the wild-type cells. Treatment with verapamil led to increased intracellular levels of daunorubicin in resistant cells, whereas an excess of N,N-dimethyldaunorubicin did not have this effect. Thus, the decreased resistance of the doxorubicin-resistant F4-6 cells to the N-alkylated anthracyclines may at least in part be due to a reduced affinity of these compounds for the efflux pump. The results indicate that the dimethylation of the amino group of the anthracycline sugar moiety and its incorporation within a morpholinyl ring may overcome MDR by similar mechanisms.

[Treatment with clonidine in a case of the short bowel syndrome with therapy-refractory diarrhea]. / Zur Behandlung mit Clonidin bei kurzdarmsyndrombedingter therapierefraktärer Diarrhö.

A patient with refractory diarrhoea (up to 10 l/d) following colectomy and ileostomy was treated with clonidine, after loperamide, tinctura opii, cholestyramine and somatostatin had failed to reduce stool volume to less than 6 l/d. Under combined treatment with clonidine (1200 micrograms/d) and somatostatin (6 mg/d), which was well tolerated, stool weights were normalised within 24 hours. This case report on the successful anti-diarrhoeic effect of clonidine is completed by experimental data from rat jejunal and duodenal segments. In the presence of the adenylate cyclase-stimulating agent forskolin, clonidine normalised both mucosal cAMP content and cAMP-induced hypersecretion in rat intestine. This suggests that the anti-diarrhoeic effect of clonidine in-vitro results from an alpha 2-receptor mediated inhibition of the stimulated adenylate cyclase. Case report and experimental data therefore support the theory that therapeutical application of clonidine in diarrhoea may be successful.

Stimulation of bile acid active transport related to increased mucosal cyclic AMP content in rat ileum in vitro.

The regulation of bile acid transport in rat ileum was studied in vitro using the adenylate cyclase stimulator forskolin, or 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Forskolin 20 microM as well as 100 microM IBMX enhanced mucosal cyclic AMP to 3-fold the control levels. As a physiological response, net fluid absorption in everted ileal sacs was reduced. Taurocholate (10-500 microM) transfer in everted perfused segments of rat ileum was measured using a three compartment dual label method suitable for measuring active transport. Transport asymmetry with absorption exceeding its counterflux by 26-fold, was measured at 500 microM taurocholate. Forskolin increased absorption of taurocholate still further, by 68%, and reduced the serosal to mucosal flux. Enhanced intracellular accumulation of taurocholate indicated a stimulatory action of forskolin on active transport at the mucosal brush-border membrane. In uptake studies, accumulation of taurocholate was enhanced by 100 microM IBMX also. Forskolin-induced uptake stimulation could also be shown for chenodeoxycholate and cholate. In the presence of the neuronal blocker tetrodotoxin, uptake stimulation was still effective. Results indicate that the ileal bile acid transporter is included within the group of sodium-dependent cotransporters of the rat small intestine which are subject to a cyclic AMP-related stimulation at the mucosal cellular level.

Evidence for adenosine A1 receptor action in rat jejunal mucosa.

Cyclic AMP was elevated in rat jejunal mucosa in the presence of adenosine deaminase (2 mg/1) both alone or under conditions of stimulated mucosal cyclic AMP accumulation (forskolin 20 microM/papaverine 100 microM). The effects of adenosine deaminase were reversed by (-)-N6-phenylisopropyl-adenosine (PIA, 10 microM). This action of PIA on mucosal cyclic AMP was antagonized by theophylline (1 mM) and was insensitive to tetrodotoxin (100 nM). The potency of PIA was 100-fold higher than that of 5'-N-ethylcarboxamido-adenosine (NECA). It is suggested that adenosine A1 receptors are present in rat jejunal mucosal cells.

Proabsorptive properties of forskolin: disposition of glycine, leucine and lysine in rat jejunum.

The effects of forskolin on mucosal cyclic AMP levels and active transport of glycine, L-lysine and L-leucine were studied in rat jejunum in vitro. Furthermore, the effects on lysine and glycine incorporation into mucosal protein and on mucosal cell volume were investigated. Elevation of intestinal mucosal cyclic AMP to threefold control levels by 10 mumol 1(-1) forskolin was accompanied by increased absorption of glycine (+33%), L-leucine (+72%) and L-lysine (+188%), as determined in a three compartment model suitable to measure active transport. Increased intracellular accumulation could be demonstrated for lysine as a transport substrate. Accordingly, using a dual label method, calculated values for uphill transport of lysine at the site of the brush border membrane were markedly enhanced. Forskolin up to 10 mumol 1(-1) had no effects on the fraction of lysine or glycine incorporated into TCA-precipitable proteins of jejunal absorptive cells. Serosal to mucosal transfer, as well as basolateral entry into mucosal cells remained unchanged for all three amino acids. Likewise, intracellular fluid space, calculated from distribution spaces for 14C-inulin and 3H2O as well as the response of cellular volume to an osmotic gradient were not affected by forskolin. As comparable stimulatory effects of forskolin on active hexose transport were reported earlier, it is suggested that forskolin - known to inhibit sodium-coupled fluid absorption - may stimulate active transport by enhancing sodium availability for sodium dependent intestinal cotransporters in general.

Response of rat small intestinal active aldohexose transport to elevation of mucosal cyclic AMP by forskolin and 3-isobutyl-1-methylxanthine in vitro.

The phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine (IBMX) was able to elevate rat small intestinal cyclic AMP levels to 300% of basal values. Active jejunal D-glucose transport was enhanced parallel to the rise of intracellular cyclic AMP levels to 140% of control values at 100 mumol/l IBMX. Transport parameters, as determined in a three compartment model in vitro using a dual label method, indicate increased 'uphill' glucose transport at the site of the brush border membrane, higher intracellular accumulation of the sugar, with unchanged passive permeabilities. Phlorizin-inhibited D-glucose transport and L-glucose transfer in the rat were not affected by the persisting cyclic AMP elevation produced by IBMX. Stimulating effects could also be demonstrated with D-galactose as a substrate. IBMX 100 mumol/l also increased active D-glucose as well as 3-O-methylglucose transport in mouse jejunum. Stimulatory effects on intestinal hexose transport and mucosal cyclic AMP levels were also found with the adenylate-cyclase activator forskolin. In the present study, forskolin effects on jejunal mucosal cyclic AMP levels were enhanced in the presence of 100 mumol/l IBMX, resulting in a 20-fold increase compared to controls at 20 mumol/l forskolin. The concentration response for the effect of forskolin in the presence of 100 mumol/l IBMX on D-glucose transport did not produce a significant increase compared to transport stimulation with IBMX alone. At higher concentrations of forskolin however, glucose transport decreased to levels well below the IBMX controls. The elevation of cellular cyclic AMP levels had no effects on passive permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Forskolin-induced elevation of rat jejunal cyclic AMP levels and stimulation of active glucose transport in vitro.

The adenylate cyclase stimulator forskolin enhanced both mucosal cyclic AMP levels and D-aldohexose transport in rat jejunum in vitro in a concentration-dependent manner. With mucosal cyclic AMP elevated to 400% of basal values, active D-glucose transport was at 200% of control values. Transport parameters, as determined in a three compartment model using a dual label method, indicate a) increased "uphill" glucose transport at the brush border membrane with higher intracellular accumulation, b) unchanged serosal to mucosal glucose fluxes and passive permeabilities. Transport stimulating effects of forskolin were also present with D-galactose in the rat. In mouse jejunum active transport of D-glucose and 3-O-methylglucose was increased by forskolin 10 mumol/l. Phlorizin inhibited D-glucose transport as well as L-glucose transport in the rat were not changed by the persisting cyclic AMP elevation induced by forskolin. The results show a positive correlation of active intestinal hexose transport with a modest elevation of mucosal cyclic AMP. In accordance to current models of cyclic AMP-induced changes in intestinal fluid absorption, rat jejunal net fluid transport was reduced by 40% with 20 mumol/l forskolin.

Effects of DDT and dieldrin on intestinal glucose transport and brush border hydrolases. A comparison with phenobarbital and methylcholanthrene.

The enhancement of in vitro small intestinal transcellular glucose transport in NMRI mice after oral administration of the organic pesticides 2,4-DDT and dieldrin can be shown to be due to an increased active transport at the site of the brush border membrane. Intestinal disaccharidase activities were concomitantly elevated in the dieldrin group, while DDT produced no effects with intestinal hydrolases. The classic enzyme inducing agents phenobarbital and methylcholanthrene failed to stimulate intestinal glucose transport, although both increased intestinal disaccharidase activities considerably, thus questioning a close relation between these digestive and absorptive functions in the translocation of glucose. Intestinal alkaline phospatase activity was enhanced after DDT, dieldrin and methylcholanthrene treatment, but not with phenobarbital. It is suggested that DDT and dieldrin exert their stimulating effect on intestinal glucose transport by a mechanism different from general induction of metabolic pathways.