Biomedical subjects

M Iscan

Publications and source records attributed to M Iscan.

11 recordsLinked to original sources

PubMed1992

Cerium-induced strain-dependent increase in Cyp2a-4/5 (cytochrome P4502a-4/5) expression in the liver and kidneys of inbred mice.

The murine Cyp2a-4 and Cyp2a-5 genes encode P450 isoforms catalysing testosterone 15 alpha-hydroxylase and coumarin 7-hydroxylase (COH) activities, respectively. Two days after the administration of a hepatotoxic dose of cerium chloride (2 mg/kg i.v.), COH activity was increased 3.2-fold in the liver of DBA/2 mice. Three and 4 days after the cerium treatment, coinciding with the occurrence of overt liver damage, there was a dramatic decrease in COH activity. The activities of testosterone 15 alpha-hydroxylase and the Cyp1a-1-mediated 7-ethoxyresorufin O-deethylase (EROD) were decreased in response to cerium. Much less pronounced changes in the enzyme activities occurred in the C57BL/6 mouse liver. Northern blot analysis showed a 21-fold increase in the hepatic Cyp2a-4/5 mRNA in the DBA/2 mice at day 2, whereas no increase occurred in the C57BL/6 mice. Also in the kidneys the increase in COH activity and in Cyp2a-4/5 mRNA was marked only in the DBA/2 mice. A polymerase chain reaction-mediated analysis method utilizing a unique PstI restriction site in the Cyp2a-5 cDNA was used to differentiate between the highly homologous Cyp2a-4 and Cyp2a-5 mRNAs. Cerium was found to increase the amount of hepatic and renal Cyp2a-4 and Cyp2a-5 mRNA only in the DBA/2 mice. These data indicate that the Cyp2a-4/5 complex is regulated in a different way in DBA/2 and C57BL/6 mice and that some association exists between the development of liver damage and COH induction.

Animals↗

PubMed1991

[Ascariasis pancreatitis. Endoscopic diagnosis and therapy].

Ascariasis lumbricoides is a parasitic disease of the human gastrointestinal tract. Migration of the worm through orifices and into ducts leads to such complications as cholangitis and pancreatitis; even bile duct perforation by Ascaris have been reported. Treatment of biliary ascariasis is usually surgical, although endoscopic removal of the worm has been successfully performed. We report on a case in whom an Ascaris worm in the common bile duct led to acute pancreatitis; the worm was successfully removed endoscopically after performing papillotomy.

Ampulla of Vater↗

PubMed1991

Distinct forms of cytochrome P-450 are responsible for 6 beta-hydroxylation of bile acids and of neutral steroids.

Cytochrome P-450-dependent 6 beta-hydroxylation of bile acids in rat liver contributes to the synthesis of the quantitatively important pool of 6-hydroxylated bile acids, as well as to the detoxification of hydrophobic bile acids. The lithocholic acid 6 beta-hydroxylation reaction was investigated and compared with androstenedione 6 beta-hydroxylation. Differential responses of these two activities to inducers and inhibitors of microsomal P-450 enzymes, lack of mutual inhibition by the two substrates and differential inhibition by antibodies raised against several purified hepatic cytochromes P-450 were observed. From these results it was concluded that 6 beta-hydroxylation of lithocholic acid is catalysed by P-450 form(s) different from the subfamily IIIA cytochromes P-450 which are responsible for the bulk of microsomal androstenedione 6 beta-hydroxylation. Similar, but more tentative, results revealed that the 7 alpha-hydroxylation of lithocholic acid and of androstenedione may be also catalysed by distinct P-450 enzymes. The results indicate that cytochromes P-450 hydroxylating bile acids are distinct from analogous enzymes that carry out reactions of the same regio- and stereo-specificity on neutral steroids (steroid hormones). A comparison of pairs of cytochromes P-450 that catalyse the same reaction on closely related steroid molecules will help to define those structural elements in the proteins that determine the recognition of their respective substrates.

Androstenedione↗

PubMed1991

Endoscopic sphincterotomy in the management of postoperative complications of hepatic hydatid disease.

The results obtained using endoscopic sphincterotomy (EST) in the management of postoperative biliary complications of hepatic hydatid disease are presented. The outcome was favourable in all eight patients treated with no associated morbidity or mortality. In three patients the clinical manifestations of cholangitis resolved, and in five of six patients the external bile fistula previously present for 26 to 68 days closed within 3 to 15 days. In one patient with a long-standing fistula (5 years) the bile outflow was reduced from 600cc to 50-100cc per day. No complications due to EST were encountered. The results show that EST can be considered the treatment of choice for biliary fistulae following surgery for hepatic hydatid disease and for drainage of bile in patients with cholangitis due to hydatid disease.

Biliary Fistula↗

PubMed1990

Human liver steroid sulphotransferase sulphates bile acids.

The sulphation of bile acids is an important pathway for the detoxification and elimination of bile acids during cholestatic liver disease. A dehydroepiandrosterone (DHEA) sulphotransferase has been purified from male and female human liver cytosol using DEAE-Sepharose CL-6B and adenosine 3',5'-diphosphate-agarose affinity chromatography [Falany, Vazquez & Kalb (1989) Biochem. J. 260, 641-646]. Results in the present paper show that the DHEA sulphotransferase, purified to homogeneity, is also reactive towards bile acids, including lithocholic acid and 6-hydroxylated bile acids, as well as 3-hydroxylated short-chain bile acids. The highest activity towards bile acids was observed with lithocholic acid (54.3 +/- 3.6 nmol/min per mg of protein); of the substrates tested, the lowest activity was detected with hyodeoxycholic acid (4.2 +/- 0.01 nmol/min per mg of protein). The apparent Km values for the enzyme are 1.5 +/- 0.31 microM for lithocholic acid and 4.2 +/- 0.73 microM for taurolithocholic acid. Lithocholic acid also competitively inhibits DHEA sulphation by the purified sulphotransferase (Ki 1.4 microM). No evidence was found for the formation of bile acid sulphates by sulphotransferases different from the DHEA sulphotransferase during purification work. The above results suggest that a single steroid sulphotransferase with broad specificity encompassing neutral steroids and bile acids exists in human liver.

Adolescent↗

PubMed1990

Regional and subcellular distribution of cytochrome P-450-dependent drug metabolism in monkey brain: the olfactory bulb and the mitochondrial fraction have high levels of activity.

In brain of female monkey (M. fascicularis) the content of cytochrome P-450 and benzo(a)pyrene hydroxylase activity in the mitochondrial fraction exceeded that of the microsomes by more than 4-fold. The mitochondrial drug metabolism activity exhibited substrate specificity and, unlike the microsomes, did not catalyze 7-ethoxyresorufin O-deethylase reaction. Moreover, the rate of benzo(a)pyrene hydroxylase activity by both the mitochondrial and the microsomal fractions displayed regional variation with the olfactory bulb displaying the highest hydroxylase activity. In contrast, the microsomal 7-ethoxyresorufin O-deethylase activity was uniformally distributed in all brain regions.

Animals↗

PubMed1990

cis-platinum-mediated decrease in serum testosterone is associated with depression of luteinizing hormone receptors and cytochrome P-450scc in rat testis.

Previously we had shown that cis-platinum decreases testosterone levels in rat serum and that hCG reverses this effect. The purpose of these studies was to determine the biochemical basis of cis-platinum-mediated effects on testicular testosterone production. In the testis of rats treated with cis-platinum (7 mg/kg, iv), the mitochondrial P-450scc concentration and side-chain cleavage activity were depressed by 40%. Also, the microsomal 17 alpha-hydroxylase activity and cytochrome P-450 concentration were decreased. Testicular binding capacity (in vitro) for [125I]hCG was decreased by 75-80%. On the other hand, FSH binding to Sertoli cell membrane receptors was not appreciably changed. hCG (25 IU/100 g daily) in treated rats caused complete occupancy of the remaining 20-25% LH receptors and caused a 20- to 30-fold increase in serum and testicular testosterone, a 2-fold increase in mitochondrial P-450scc, and a 5-fold acceleration of side-chain cleavage activity. 17 alpha-Hydroxylase activity and microsomal cytochrome P-450 were not increased over the control values. In addition to testicular functions, pituitary glycoprotein hormone production was assessed. Treatment of rats with cis-platinum (7 mg/kg, iv) did not change serum LH or FSH, but caused a 50% decrease in serum and testicular testosterone levels. A GnRH challenge test (1.5 micrograms/100 g, in 30 min) of treated rats caused prompt increases of 10- to 15-fold in serum LH and resulted in increases in serum and testicular testosterone. Thus, there was little evidence for cis-platinum effects at the level of hypothalamus or pituitary that could account for the decreased testosterone production. Reversal of the cis-platinum effect on steroidogenesis by hCG or GnRH appears to be due to the induction of suprasaturating levels of LH with full occupancy of remaining Leydig cell LH receptors. This, in turn, would reverse the diminished levels of mitochondrial side-chain cleavage activity and cytochrome P-450scc. These data suggest that cis-platinum causes a depression in serum testosterone, mainly by decreasing the number of LH receptors and inhibiting side-chain cleavage activity.

Animals↗

PubMed1990

Differential regulation of heme and drug metabolism in rat testis and prostate: response to cis-platinum and human chorionic gonadotropin.

In the absence of notable changes in heme metabolic activities in the testes of rats treated with cis-platinum (7 mg/kg i.v.) and sacrificed after 1, 3 or 7 days, time-dependent decreases in the activity of benzo(a)pyrene hydroxylase (AHH), ethoxyresorufin O-deethylase (7-ERDE) and the concentration of cytochrome P-450 were observed. In contrast, in the prostate of the treated rats, despite reductions in the activity of heme oxygenase and that of enzymes of heme biosynthetic pathway, biotransformation of benzo(a)pyrene and ethoxyresorufin and cytochrome P-450 concentration were not altered. cis-Platinum treatment (7 days) also decreased markedly the serum and testicular testosterone levels (50-70%). Human chorionic gonadotropin (hCG, 25 IU/100 g/day for 7 days) given to the treated rats (7 days) caused a 5- to 15-fold increase in the serum and testicular testosterone levels and reversed the spectrum of the aforementioned inhibitory effects of cis-platinum on heme metabolic enzymes. The response of the testis and prostate drug metabolic activities to hCG treatment also differed. In the testis of cis-platinum-treated rats, the inhibited AHH and 7-ERDE activities were reversed by hCG treatment and cytochrome P-450 concentration returned to the control level. In the prostate, however, hCG treatment neither changed AHH and 7-ERDE activities nor the concentration of the microsomal cytochrome P-450. In addition, in the testis the pattern of response of AHH and 7-ERDE activities to hCG was dissimilar; whereas 7-ERDE activity returned to the normal level, AHH activity surpassed the normal activity and reached a near 2.5-fold increase over the control value.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Aminolevulinate Synthetase↗

PubMed1989

Benzo[a]pyrene-DNA-adducts and monooxygenase activities in mice treated with benzo[a]pyrene, cigarette smoke or cigarette smoke condensate.

Synchronous fluorescence spectrophotometry (SFS), developed to study benzo[a]pyrene-7,8-diol-9,10-epoxide(BPDE)-DNA, was used to measure the in vivo formation of DNA-adducts in genetically responsive C57BL/6 (B6) and non-responsive DBA/2 (D2) mice. Treatment with cigarette smoke by inhalation for 3-16 days, or i.p. injection of cigarette smoke condensate or neutral fraction did not lead to detectable levels of BPDE-DNA-adducts in either lungs or liver, although aryl hydrocarbon hydroxylase (AHH) activity, an indicator of benzo[a]pyrene (BP) metabolism, was clearly induced in lungs of B6 mouse. A dose-dependent amount of BPDE-DNA-adducts in lung and somewhat less in liver was found after i.p. injection with BP (20-80 mg/kg). Mice treated with vehicle or 4 mg/kg of BP were negative for adducts by SFS. In B6 mice AHH was induced both in lungs and livers while there was no AHH induction in D2 mice although the levels of BPDE-DNA-adducts were somewhat higher than in B6 mice. Thus, no clear correlation seems to exist between AHH activity and the formation of BPDE-DNA-adducts. Also, according to our results SFS can be used to quantitate adduct-formation in in vivo animal studies.

7-Alkoxycoumarin O-Dealkylase↗

PubMed1989

Effects of 2-arylbenzimidazoles on rat hepatic microsomal monooxygenase system.

1. The effects of eight newly synthesized 2-aryl substituted benzimidazole derivatives on control and phenobarbital (PB) treated rat liver microsomal aniline 4-hydroxylase and ethylmorphine N-demethylase activities, and their binding to control and PB-treated rat liver microsomal oxidized cytochrome P-450 are presented. 2. All compounds inhibited ethylmorphine N-demethylase activity with I50 values ranging from 8.50 x 10(-4) M to 27.83 x 10(-4) M in control and ranging from 2.80 x 10(-4) M to 15.79 x 10(-4) M in PB-treated rats. 3. Aniline 4-hydroxylase activity was inhibited by all of the compounds tested having I50 values in the range of 7.04 x 10(-4) M-31.37 x 10(-4) M in PB-treated rats, but only five of the compounds showed inhibitory activity in control rats. 4. Only a few significant regression coefficients could be found between the parameters of the chemicals studied and their inhibitory patterns. 5. No correlation has been observed between the binding of the derivatives and their inhibitory pattern.

Aniline Hydroxylase↗

PubMed1988

Inhibition of human hepatic and placental xenobiotic monooxygenases by imidazole antimycotics.

Three imidazole antimycotic drugs, ketoconazole, clotrimazole and miconazole, were studied to characterize the inhibition of aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECDE) and 7-ethoxyresorufin O-deethylase (ERDE) activities in human liver and placenta in vitro in comparison with liver enzymes from control, phenobarbital (PB) and 3-methylcholanthrene (MC) pretreated rats. All three compounds inhibited rat liver enzymes, although MC pretreatment seemed to lead to a resistance of inhibition relative to PB-treated and control animals. There were large differences in the extent of inhibition of human hepatic and placental activities. Furthermore, while the type of inhibition of the hepatic ERDE was competitive or mixed, that of the placental enzyme cannot be described in ordinary terms of inhibition kinetics. Ketoconazole and clotrimazole were relatively potent inhibitors of maternal cigarette smoking-induced placental ECDE activities (IC50 values from 0.5 microM to 5 microM), whereas much less inhibition of the placental AHH activity was obtained with ketoconazole and miconazole (IC50 values from 50 microM to 500 microM). In most cases, hepatic enzymes were less sensitive to antimycotics than placental activities. This was in contrast with results from rat enzyme studies, in which MC pretreatment seemed to decrease the inhibitory response.

7-Alkoxycoumarin O-Dealkylase↗