Publications

• Chiral sulfoxidation of albendazole by the flavin adenine dinucleotide-containing and cytochrome P450-dependent monooxygenases from rat liver microsomes.

  Moroni P., Buronfosse T., Longin-Sauvageon C., Delatour P., Benoit E.

  The enantioselectivity of the in vitro sulfoxidation of the prochiral drug albendazole was investigated in rat liver microsomes. When biological material obtained from control rats and phenobarbital-, 3-methylcholanthrene-, or dexamethazone-pretreated rats was subjected to specific immunological a ... >> More

  The enantioselectivity of the in vitro sulfoxidation of the prochiral drug albendazole was investigated in rat liver microsomes. When biological material obtained from control rats and phenobarbital-, 3-methylcholanthrene-, or dexamethazone-pretreated rats was subjected to specific immunological and chemical inhibitors, it was shown that two main enzymatic systems--cytochrome P450s and flavin-containing monooxygenase (FMO)--were responsible for the sulfoxidation. Purified FMO from rat liver was used to study the enantioselectivity of this enzyme in the sulfoxidation of albendazole. The enantiospecificity of FMO is the reverse of that of the P450s. Nevertheless, each P450 isoenzyme involved in this reaction presents its own individual stereoselectivity. << Less

  Drug Metab. Dispos. 23:160-165(1995) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• Identification of novel substrates for human cytochrome P450 2J2.

  Lee C.A., Neul D., Clouser-Roche A., Dalvie D., Wester M.R., Jiang Y., Jones J.P. III, Freiwald S., Zientek M., Totah R.A.

  Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential C ... >> More

  Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential CYP2J2 substrates. Eight novel substrates were identified that vary in size and overall topology from relatively rigid structures (amiodarone) to larger complex structures (cyclosporine). The substrates displayed in vitro intrinsic clearance values ranging from 0.06 to 3.98 mul/min/pmol CYP2J2. Substrates identified for CYP2J2 are also metabolized by CYP3A4. Extracted ion chromatograms of metabolites observed for albendazole, amiodarone, astemizole, thioridazine, mesoridazine, and danazol showed marked differences in the regioselectivity of CYP2J2 and CYP3A4. CYP3A4 commonly metabolized compounds at multiple sites, whereas CYP2J2 metabolism was more restrictive and limited, in general, to a single site for large compounds. Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. For albendazole, CYP2J2 forms a unique metabolite compared with CYP3A4. Albendazole and amiodarone were evaluated in various in vitro systems including recombinant CYP2J2 and CYP3A4, pooled human liver microsomes (HLM), and human intestinal microsomes (HIM). The Michaelis-Menten-derived intrinsic clearance of N-desethyl amiodarone was 4.6 greater in HLM than in HIM and 17-fold greater in recombinant CYP3A4 than in recombinant CYP2J2. The resulting data suggest that CYP2J2 may be an unrecognized participant in first-pass metabolism, but its contribution is minor relative to that of CYP3A4. << Less

  Drug Metab. Dispos. 38:347-356(2010) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes.

  Miyazawa M., Shindo M., Shimada T.

  1,8-Cineole, the monoterpene cyclic ether known as eucalyptol, is one of the components in essential oils from Eucalyptus polybractea. We investigated the metabolism of 1,8-cineole by liver microsomes of rats and humans and by recombinant cytochrome P450 (P450 or CYP) enzymes in insect cells in wh ... >> More

  1,8-Cineole, the monoterpene cyclic ether known as eucalyptol, is one of the components in essential oils from Eucalyptus polybractea. We investigated the metabolism of 1,8-cineole by liver microsomes of rats and humans and by recombinant cytochrome P450 (P450 or CYP) enzymes in insect cells in which human P450 and NADPH-P450 reductase cDNAs had been introduced. 1,8-Cineole was found to be oxidized at high rates to 2-exo-hydroxy-1,8-cineole by rat and human liver microsomal P450 enzymes. In rats, pregenolone-16alpha-carbonitrile (PCN) and phenobarbital induced the 1,8-cineole 2-hydroxylation activities by liver microsomes. Several lines of evidence suggested that CYP3A4 is a major enzyme involved in the oxidation of 1,8-cineole by human liver microsomes: (1), 1,8-cineole 2-hydroxylation activities by liver microsomes were inhibited very significantly by ketoconazole, a CYP3A inhibitor, and anti-CYP3A4 immunoglobulin G; (2), there was a good correlation between CYP3A4 contents and 1,8-cineole 2-hydroxylation activities in liver microsomes of eighteen human samples; and (3), of various recombinant human P450 enzymes examined, CYP3A4 had the highest activities for 1,8-cineole 2-hydroxylation; the rate catalyzed by CYP3A5 was about one-fourth of that catalyzed by CYP3A4. Kinetic analysis showed that K(m) and V(max) values for the oxidation of 1,8-cineole by liver microsomes of human sample HL-104 and rats treated with PCN were 50 microM and 91 nmol/min/nmol P450 and 20 microM and 12 nmol/min/nmol P450, respectively. The rates observed using human liver microsomes and recombinant CYP3A4 were very high among other CYP3A4 substrates reported so far. These results suggest that 1,8-cineole, a monoterpenoid present in nature, is one of the effective substrates for CYP3A enzymes in rat and human liver microsomes. << Less

  Drug Metab. Dispos. 29:200-205(2001) [PubMed] [EuropePMC]

  This publication is cited by 5 other entries.

• Relative contribution of cytochromes P-450 and flavin-containing monooxygenases to the metabolism of albendazole by human liver microsomes.

  Rawden H.C., Kokwaro G.O., Ward S.A., Edwards G.

  <h4>Aims</h4>Albendazole (ABZ; methyl 5-propylthio-1H-benzimidazol-2-yl carbamate) is a broad spectrum anthelmintic whose activity resides both in the parent compound and its sulphoxide metabolite (ABS). There are numerous reports of ABZ metabolism in animals but relatively few in humans. We have ... >> More

  <h4>Aims</h4>Albendazole (ABZ; methyl 5-propylthio-1H-benzimidazol-2-yl carbamate) is a broad spectrum anthelmintic whose activity resides both in the parent compound and its sulphoxide metabolite (ABS). There are numerous reports of ABZ metabolism in animals but relatively few in humans. We have investigated the sulphoxidation of ABZ in human liver microsomes and recombinant systems.<h4>Methods</h4>The specific enzymes involved in the sulphoxidation of ABZ were determined by a combination of approaches; inhibition with an antiserum directed against cytochrome P450 reductase, the effect of selective chemical inhibitors on ABZ sulphoxidation in human liver microsomes, the capability of expressed CYP and FMO to mediate the formation of ABS, regression analysis of the rate of metabolism of ABZ to ABS in human liver microsomes against selective P450 substrates and regression analysis of the rate of ABS sulphoxidation against CYP expression measured by Western blotting.<h4>Results</h4>Comparison of Vmax values obtained following heat inactivation (3min at 45 degrees C) of flavin monoxygenases (FMO), chemical inhibition of FMO with methimazole and addition of an antiserum directed against cytochrome P450 reductase indicate that FMO and CYP contribute approximately 30% and 70%, respectively, to ABS production in vitro. Comparison of CLint values suggests CYP is a major contributor in vivo. A significant reduction in ABZ sulphoxidation (n = 3) was seen with ketoconazole (CYP3 A4; 32-37%), ritonavir (CYP3 A4: 34-42%), methimazole (FMO: 28-49%) and thioacetamide (FMO; 32-35%). Additive inhibition with ketoconazole and methimazole was 69 +/-8% (n = 3). ABS production in heat - treated microsomes (3 min at 45 degrees C) correlated significantly with testosterone 6beta-hydroxylation (CYP3A4; P < 0.05) and band intensities on Western blots probed with an antibody selective for 3A4 (P < 0.05). Recombinant human CYP3 A4, CYP1A2 and FMO3 produced ABS in greater quantities than control microsomes, with those expressing CYP3A4 producing threefold more ABS than those expressing CYP1A2. Kinetic studies showed the Km values obtained with both CYP3A4 and FMO3 were similar.<h4>Conclusions</h4>We conclude that the production of ABS in human liver is mediated via both FMO and CYP, principally CYP3A4, with the CYP component being the major contributor. << Less

  Br. J. Clin. Pharmacol. 49:313-322(2000) [PubMed] [EuropePMC]

  This publication is cited by 2 other entries.

• CYP2J2 and CYP2C19 are the major enzymes responsible for metabolism of albendazole and fenbendazole in human liver microsomes and recombinant P450 assay systems.

  Wu Z., Lee D., Joo J., Shin J.H., Kang W., Oh S., Lee D.Y., Lee S.J., Yea S.S., Lee H.S., Lee T., Liu K.H.

  Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite for ... >> More

  Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo. << Less

  Antimicrob. Agents Chemother. 57:5448-5456(2013) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Induction of cytochrome P450 enzymes by albendazole treatment in the rat.

  Asteinza J., Camacho-Carranza R., Reyes-Reyes R.E., Dorado-Gonzalez V., Espinosa-Aguirre J.J.

  The anthelmintic drug albendazole (ABZ), methyl(5-(propylthio)-1H-benzimidazol-2-yl)carbamate, is a benzimidazole highly efficient in the treatment of neurocysticercosis. The effects of ABZ treatment (i.p. and p.o. administration) on the expression of several cytochrome P450 (CYP) enzymes were eva ... >> More

  The anthelmintic drug albendazole (ABZ), methyl(5-(propylthio)-1H-benzimidazol-2-yl)carbamate, is a benzimidazole highly efficient in the treatment of neurocysticercosis. The effects of ABZ treatment (i.p. and p.o. administration) on the expression of several cytochrome P450 (CYP) enzymes were evaluated in rat liver in order to characterize the spectrum of altered CYP enzymes involved in the metabolism of environmental mutagens and carcinogens, after drug intake. Intraperitoneal administration of ABZ (50 mg/kg body weight/day/three days in corn oil) to rats, caused an induction of hepatic activities of CYP1A1-associated ethoxyresorufin O-deethylase (EROD) 65 fold, CYP1A2-associated methoxyresorufin O-demethylase (MROD) 6 fold, CYP2B1-associated penthoxyresorufin O-dealkylase (PROD) 4 fold, CYP2B2-associated benzyloxyresorufin O-dealkylase (BROD) 14 fold, as well as a partial reduction of CYP2E1-associated 4-nitrophenol hydroxylase (4-NPH) activity. CYP3A-associated erythromycin N-demethylase (END) activity was not modified under the same treatment conditions. Western blot analysis was conducted to explore if the increased catalytic activity was a result of an increased protein content; only CYP1A1/2 showed a visible increase in protein concentration after ABZ inoculation, therefore, the increased PROD and BROD activities could be attributed to the induction of CYP1A1/2. Results with the two main metabolites of ABZ (15 mg/kg body weight/day/three days, i.p.) indicated that ABZ sulfoxide (ABZSO) but not ABZ sulfone (ABZSO(2)) displayed the same pattern of CYP induction than ABZ. Oral administration of ABZ at the human therapeutic dose of 20 mg/kg body weight/day/three days, produced an increase in CYP1A1/2 protein content 24 h after the first intake. The protein level remained high during the treatment, and up to 72 h after the last administration; basal protein levels were almost recovered 48 h later. << Less

  Environ Toxicol Pharmacol 9:31-37(2000) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.