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Biomedical subjects

G F Kahl

Publications and source records attributed to G F Kahl.

At least 19 recordsLinked to original sources
PubMed1992

Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma.

The development of colon carcinomas is associated with allelic deletions on chromosomes 5q, 17p, and 18q. The DCC gene located on chromosome 18q21.3 codes for a potential tumor suppressor gene related to cellular adhesion receptors. We investigated the expression of this gene in several pancreatic carcinoma cell lines and in patients with ductal adenocarcinomas of the pancreas. In 8 of 11 cell lines and in 4 of 8 primary tumors a complete extinction of DCC gene expression was observed, whereas the c-Ki-ras gene was mutated at codon 12 in 7 of 8 tumors. A highly reduced or absent expression of DCC was found in all low or undifferentiated pancreatic tumor cell lines, whereas in the more differentiated ones DCC expression was conserved. These data suggest that loss of DCC gene expression is an important factor in the development or progress of pancreatic adenocarcinoma and may be linked to the differentiated phenotype of the pancreatic tumor cell.

Carcinoma, Intraductal, Noninfiltrating↗
PubMed1991

Kinetics of melphalan leakage during hyperthermic isolation perfusion in melanoma of the limb.

The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 micrograms/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 micrograms/ml (with cisplatin) in lower extremity perfusion. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been terminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.

Adult↗
PubMed1991

Nicotine metabolism in isolated perfused lung and liver of phenobarbital- and benzoflavone-treated rats.

The kinetics of nicotine elimination was investigated in isolated perfused lung and liver of phenobarbital (PB)- and 5,6-benzoflavone (BF)-pretreated rats. The estimated kinetic parameters demonstrated a high nicotine elimination rate in rat lung approaching the capacity of liver when both organs were in an uninduced state. The concentration-time profiles of cotinine as the main metabolite were almost identical for isolated lung and liver. In both organs the cotinine plasma concentrations reached a plateau level after 60 min of perfusion. Pretreatment of rats with 5,6-benzoflavone did not affect the rate of nicotine elimination and cotinine formation either in the lung or in the liver. Phenobarbital treatment, however, induced nicotine clearance in lung approximately 2-fold. This effect is quantitatively lower than the PB-related 8-fold induction of hepatic nicotine elimination observed in a previous study. The present results also indicate that the turnover of cotinine is markedly enhanced after PB induction. The elimination half-lives and clearance values for cotinine as the substrate were approximately 10-fold increased in rat liver after PB pretreatment. Thus, an important contribution of extrahepatic tissues to nicotine metabolism in rats has to be assumed. Moreover, since cotinine elimination is significantly increased after PB induction it is questionable whether cotinine plasma concentrations can further be used as suitable parameter for nicotine consumption.

Animals↗
PubMed1990

Determination of 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 3'-fluoro-3'-deoxythymidine and 2',3'-dideoxyinosine in biological samples by high-performance liquid chromatography.

A simple and fast high-performance liquid chromatographic assay for the determination of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 3'-fluoro-3'-deoxythymidine (FT) and 2',3'-dideoxy-inosine (ddI) in complex biological matrices is described. The method allows rapid nucleoside determination using a phenyl column within extra- as well as intracellular media without further sample pretreatment and extraction procedures. The lower limit of detection is ca. 0.05 micrograms/ml for each nucleoside, and the separation can easily be optimized for AZT, ddC, FT and ddI by variation of the methanolic part of the mobile phase and the detector wavelengths.

Animals↗
PubMed1990

Regulation of cytochrome P-450 CYPIA1 gene expression and proto-oncogene expression by growth factors in primary hepatocytes.

The effect of growth factors on the cytochrome P-450 (CYPIA1) gene expression was studied in primary mouse hepatocytes. Of the three growth factors used, i.e. epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha) and insulin, only EGF or TGF alpha completely blocked CYPIA1 expression in the presence of the CYPIA1 inducer 3-methylcholanthrene (3-MC). This repression was not linked to cell cycle progression of the hepatocyte because insulin was active to induce 'early immediate genes' and DNA replication as well as EGF/TGF alpha but failed to suppress CYPIA1 expression. A specific EGF/TGF alpha receptor-mediated function may repress CYPIA1 gene expression and contribute to the acquisition of a xenobiotic drug resistance phenotype.

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↗
PubMed1990

Nonlinear elimination kinetics of 5-fluoro-2'-deoxyuridine in isolated perfused rat liver and isolated hepatocytes.

The kinetic parameters of the cytostatic agent 5-fluoro-2'-deoxyluridine (FUDR) were studied in isolated rat hepatocytes and in the isolated perfused rat liver. In both experimental setups a dose dependency of the elimination parameters, half-life and clearance, was observed with a calculated turning point around 250 microM. In the medium of rat hepatocytes incubated at low (0.1 microM) to high (2000 microM) FUDR, the majority of the metabolites consisted of the catabolite alpha-fluoro-beta-alanine. The nucleobase metabolites, 5-fluorouracil and its primary product 5,6-dihydro-5-fluorouracil, approached apparent steady-state levels comprising 10 to 15% of the initial concentration. In the intracellular phase of hepatocytes incubated at 300 microM FUDR almost 90% of the FUDR-derived material was alpha-fluoro-beta-alanine, whereas essentially no unchanged FUDR could be detected. Similar results were obtained at extracellular FUDR concentrations exceeding 300 microM. In the isolated perfused rat liver, the clearance decreased to 15 to 20% of the corresponding values when the initial concentration was raised from 24 to 2400 microM. At the end of perfusion alpha-fluoro-beta-alanine comprised 90 to 95% of FUDR-derived total radioactivity in the tissue even at initially 2400 microM FUDR, although at this FUDR dosage 20% of the substrate remained unmetabolized in the medium. These results suggest that the limitation of hepatic FUDR elimination is not due to saturable hepatic metabolism but must be due to saturable uptake of these pyrimidine derivatives across the cellular membrane of parenchymal liver cells.

Animals↗
PubMed1988

Pharmacokinetics of low doses of benzo[a]pyrene in the rat.

Intestinal absorption, bioavailability, hepatic and pulmonary extraction and elimination of low doses of benzo[a]pyrene (BP; 0.7-4.4 nmol) were studied in the rat using [G-3H]BP. The hepatic extraction ratio was 0.4 both in a liver perfusion model and in vivo as determined by comparison of intravenous and intraportal infusion experiments in anaesthetized rats. The pulmonary extraction ratio in vivo was 0.11 in control rats and 0.16 in rats pretreated with an inducer of cytochrome P-448. Analysis of BP concentrations in atrial blood and in the bile after continuous BP infusion into the duodenum of anaesthetized rats indicated that at least 30% of the dose must have been absorbed from the gut. Studies have also been performed in conscious rats given BP either as an intravenous bolus or by gavage. The bioavailability was determined to be about 10% in these experiments. Elimination proceeded in a triphasic manner with a half-life of 16.6 hr for the terminal phase.

Administration, Oral↗
PubMed1988

Inhibitory effect of nicotine on benzo(a)pyrene elimination and marked pulmonary metabolism of nicotine in isolated perfused rat lung.

Concomitant administration of nicotine to the perfusion medium of an isolated perfused rat lung decreased the pulmonary elimination of benzo(a)pyrene entering the lung by vascular access. This inhibitory effect of nicotine was observed at a concentration of 0.5 microM nicotine in the perfusion medium. The elimination half-life of benzo(a)pyrene given as a bolus to establish an initial concentration of 1 microM in the perfusate was increased by a factor of about 3 after the addition of nicotine at 60 min of perfusion. A comparably high increase of the benzo(a)pyrene steady-state concentration was observed during constant infusion experiments when nicotine as the interfering substrate was infused parallelly after a control period of 60 min. In perfused rat lungs the rate of metabolism of nicotine given as a bolus (initial concentration of 0.5 microM) was comparable to the rate in isolated rat livers for 5,6-benzoflavone, oil or saline pretreated animals. Induction of cytochrome P-450 by pretreatment of the rats with phenobarbital caused an eightfold increase of the nicotine clearance in isolated livers, whereas the pulmonary nicotine clearance was almost doubled. Overall, expressed per g organ weight, the isolated perfused rat lung exhibited a marked capacity to metabolize nicotine while even the maximally induced phenobarbital-stimulated rat liver reached only 60% of the corresponding clearance values (per g organ) of the isolated rat lung. For the 5,6-benzoflavone and control treatments, values of 14%-21% were estimated for the liver compared with lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Eightfold induction of nicotine elimination in perfused rat liver by pretreatment with phenobarbital.

Elimination of nicotine by isolated rat livers was increased eightfold after pretreatment with phenobarbital (PB) as an inducer of cytochrome P-450 while it was only marginally influenced after pretreatment with 5,6-benzoflavone (BF) as an inducer of cytochrome P-448. Initial rates of cotinine formation were enhanced in the same order of magnitude in PB-induced livers. The 14C-nicotine-derived radioactivity excreted into bile within 2 h ranged between 6 -17% of the dose with only 2.7 fold higher values after PB pretreatment compared to controls.

Animals↗
PubMed1987

Comparison of benzo(a)pyrene metabolism in isolated perfused rat lung and liver.

The metabolism of 1 mM benzo(a)pyrene was studied in isolated perfused lung and liver of 5,6-benzoflavone-pretreated rats. Benzo(a)pyrene metabolism by the liver was more rapid than by the lung, but total metabolite formation in the lung at the end of a 120-min perfusion period was comparable to that in the liver. Lung perfusate was characterized by high concentrations of free metabolites, with diols outweighing phenols; in liver perfusate free metabolite concentrations were low, and large quantities of metabolites were found as conjugates in the bile at the end of perfusion. The tissue concentrations of free diols and phenols including the precursors of the main DNA-binding secondary metabolites were higher in the lung than in the liver. These findings explain the similar level of covalent binding in perfused lung and liver previously described (Klaus et al. 1982).

Animals↗
PubMed1987

Metabolism of benzo[a]pyrene in the combined rat liver--lung perfusion system.

The influence of the insertion of a liver into the perfusion circuit of a lung on the availability of benzo[a]pyrene and benzo[a]pyrene metabolites to the lung was examined. Perfused lungs from 5,6-benzoflavone pretreated rats release high quantities of free benzo[a]pyrene metabolites and conjugates into the perfusion medium. The insertion of a liver taken from an untreated rat reduces the concentration of unmetabolized substrate and of free diol, quinone and phenol metabolites to less than 20% of the concentrations found in the absence of the liver. When the liver of a 5,6-benzoflavone-pretreated rat is used, substrate depletion is not much greater than in the experiments with control livers; however, the concentration of free metabolites is further reduced to one third. In lung tissue, only very low levels of benzo[a]pyrene and greatly reduced levels of free and conjugated metabolites are found when a 5,6-benzoflavone-induced liver had been present during perfusion. These findings can explain the protective effect of the liver on covalent binding of benzo[a]pyrene metabolites to pulmonary macro-molecules observed in previous experiments with the combined liver-lung perfusion model [Klaus et al., Biochem. Biophys. Res. Commun., 105 (1982) 596].

Animals↗
PubMed1978

Binding of benzo(a)pyrene metabolites to cellular DNA in perfused rat lungs.

The influence of pretreatment with monooxygenase inducers on total irreversible binding of metabolically activated [3H]-benzo(a)pyrene to cellular DNA and the formation of benzo(a)pyrene metabolite-deoxyribonucleoside adducts after cytochrome P-448 induction was studied in perfused rat lungs. Pretreatment with the cytochrome P-448 inducer beta-naphthoflavone increasing binding by a factor of 23. In lungs of induced animals, 0.45 pmoles of benzo(a)pyrene equivalents were bound per mg DNA. Binding to RNA and to protein was also considerably induced by beta-naphthoflavone. Phenobarbital treatment did not significantly increase binding to cellular macromolecules of rat lung. Analysis of hydrolyzed DNA of lungs from beta-naphthoflavone-treated rats by Sephadex LH 20 chromatography revealed the formation of at least two nucleoside adducts with metabolically activated benzo(a)pyrene one of which is probably due to modification of the DNA with a benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide and the other to modification of DNA with secondary metabolites of benzo(a)pyrene phenols.

Animals↗
PubMed1978

Differential inhibition of biphenyl hydroxylation in perfused rat liver.

A differential inhibition of biphenyl hydroxylation by alpha-naphthoflavone and metyrapone was observed in isolated perfused rat liver. alpha-Naphthoflavone inhibited 2- and 4-hydroxylation in livers from beta-naphthoflavone-pretreated animals but had no effect on both reactions in livers from phenobarbital-pretreated animals. Metyrapone inhibited 2- and 4-hydroxylation in phenobarbital-stimulated livers, but only insignificant inhibition of 2-hydroxylation and a slight enhancement of 4-hydroxylation by metyrapone was observed in beta-naphthoflavone-stimulated livers. Conjugation of 2-hydroxybiphenyl and 4-hydroxybiphenyl by isolated perfused livers was also studied. 4-Hydroxybiphenyl preferentially formed sulphates in livers from untreated animals but after induction glucuronidation was as effective as sulphation or even exceeded sulphation. Only glucuronic acid conjugates of 2-hydroxybiphenyl were detected.

Animals↗