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Article ; Online: A Pharmacokinetics-Time to Alleviation of Symptoms Model to Support Extrapolation of Baloxavir Marboxil Clinical Efficacy in Different Ethnic Groups with Influenza A or B.

Retout, Sylvie / De Buck, Stefan / Jolivet, Sébastien / Duval, Vincent / Cosson, Valérie

2022 Volume 112, Issue 2, Page(s) 372–381

Abstract: Baloxavir marboxil, the prodrug of baloxavir acid, is an anti-influenza antiviral. Here, a pharmacokinetics-time to alleviation of symptoms (PK-TTAS) model was developed and used to (I) characterize the PK-TTAS relationship, (II) quantify the impact of ... ...

Abstract	Baloxavir marboxil, the prodrug of baloxavir acid, is an anti-influenza antiviral. Here, a pharmacokinetics-time to alleviation of symptoms (PK-TTAS) model was developed and used to (I) characterize the PK-TTAS relationship, (II) quantify the impact of covariates, and (III) predict TTAS in different ethnic groups. Data from 1781 otherwise-healthy (OwH) or high-risk (HR) patients included in phase II (JapicCTI-153090) and III studies (NCT02954354 and NCT02949011) were used; patients received either placebo or oral baloxavir marboxil. The natural distribution of TTAS in placebo-treated patients was modeled, then TTAS data from the baloxavir marboxil arms were added to model the impact of baloxavir acid concentration on TTAS. PK parameters estimated by a population PK model and informed by phase I data (NCT03959332 and KCT0003535) were included to simulate TTAS in Chinese and South Korean patients. Composite symptom score at baseline (TSS0), ethnicity, sex, and patient type (OwH or HR) significantly impacted the natural TTAS distribution. TTAS reduced with increasing baloxavir acid concentrations. Compared with placebo, high and low baloxavir acid exposures (AUC
MeSH term(s)	Antiviral Agents/pharmacokinetics ; Antiviral Agents/therapeutic use ; Clinical Studies as Topic ; Dibenzothiepins/pharmacokinetics ; Dibenzothiepins/therapeutic use ; Ethnicity ; Humans ; Influenza A virus ; Influenza B virus ; Influenza, Human/drug therapy ; Influenza, Human/ethnology ; Morpholines/pharmacokinetics ; Morpholines/therapeutic use ; Pyridones/pharmacokinetics ; Pyridones/therapeutic use ; Treatment Outcome ; Triazines/pharmacokinetics ; Triazines/therapeutic use
Chemical Substances	Antiviral Agents ; Dibenzothiepins ; Morpholines ; Pyridones ; Triazines ; baloxavir (4G86Y4JT3F)
Language	English
Publishing date	2022-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.2648
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Article ; Online: Pharmacokinetics, safety, and simulated efficacy of an influenza treatment, baloxavir marboxil, in Chinese individuals.

Liu, Yanmei / Retout, Sylvie / Duval, Vincent / Jia, Jingying / Zou, Yang / Wang, Yijun / Cosson, Valérie / Jolivet, Sébastien / De Buck, Stefan

Clinical and translational science

2022 Volume 15, Issue 5, Page(s) 1196–1203

Abstract: Baloxavir marboxil is an endonuclease inhibitor indicated for the treatment of influenza in patients ≥12 years. No data exist for Chinese patients in global studies. This randomized, open-label, phase I study evaluated the pharmacokinetics (PK) and ... ...

Abstract	Baloxavir marboxil is an endonuclease inhibitor indicated for the treatment of influenza in patients ≥12 years. No data exist for Chinese patients in global studies. This randomized, open-label, phase I study evaluated the pharmacokinetics (PK) and safety of baloxavir marboxil in healthy Chinese volunteers and was used to anticipate efficacy in Chinese patients. Patients received a single oral dose of baloxavir marboxil (40 or 80 mg [1:1]). Serial blood samples were collected predose and at various timepoints up to 14 days postdose. Baloxavir marboxil and acid plasma concentrations were determined by liquid chromatography tandem mass spectrometry. PK parameters of baloxavir acid were estimated by noncompartmental analysis. Adverse events (AEs) were recorded. Time to alleviation of symptoms (TTAS) was simulated for otherwise healthy (OwH) and high-risk (HR) Chinese and Asian patients. Thirty-two male patients received baloxavir marboxil. Baloxavir acid plasma concentration peaked 4 h postdose. Mean maximum concentration (C
MeSH term(s)	Antiviral Agents ; China ; Dibenzothiepins/adverse effects ; Humans ; Influenza, Human/drug therapy ; Male ; Morpholines ; Pyridones/adverse effects ; Triazines
Chemical Substances	Antiviral Agents ; Dibenzothiepins ; Morpholines ; Pyridones ; Triazines ; baloxavir (4G86Y4JT3F)
Language	English
Publishing date	2022-02-19
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.13237
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Article ; Online: Population Pharmacokinetics and Exposure-Response Relationships of Baloxavir Marboxil in Influenza Patients at High Risk of Complications.

Koshimichi, Hiroki / Retout, Sylvie / Cosson, Valerie / Duval, Vincent / De Buck, Stefan / Tsuda, Yoshiyuki / Ishibashi, Toru / Wajima, Toshihiro

Antimicrobial agents and chemotherapy

2020 Volume 64, Issue 7

Abstract: Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population ... ...

Abstract	Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11,846 plasma concentration data items from 1,827 subjects, including 2,341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications. Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients. The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.
MeSH term(s)	Antiviral Agents/therapeutic use ; Dibenzothiepins ; Humans ; Influenza, Human/drug therapy ; Morpholines ; Pyridones/therapeutic use ; Triazines/therapeutic use
Chemical Substances	Antiviral Agents ; Dibenzothiepins ; Morpholines ; Pyridones ; Triazines ; baloxavir (4G86Y4JT3F)
Language	English
Publishing date	2020-06-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.00119-20
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: CYP3A but not P-gp plays a relevant role in the in vivo intestinal and hepatic clearance of the delta-specific phosphoinositide-3 kinase inhibitor leniolisib.

De Buck, Stefan / Kucher, Klaus / Hara, Hisanori / Gray, Cathy / Woessner, Ralph

Biopharmaceutics & drug disposition

2018 Volume 39, Issue 8, Page(s) 394–402

Abstract: This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P-gp, ...

Abstract	This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P-gp, the potential interaction with quinidine, a strong inhibitor of P-gp but not CYP3A, was studied as well. Using a fixed-sequence, 3-way crossover design, 20 healthy male subjects received single oral doses of 10 mg leniolisib during three phases separated by a washout: (1) leniolisib alone, (2) 200 mg itraconazole once daily for 9 days plus leniolisib on day 5, and (3) 300 mg quinidine administered 1 h before and 3 h after leniolisib. Itraconazole increased the leniolisib oral drug exposure (AUC
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Adolescent ; Adult ; Cross-Over Studies ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Humans ; Intestinal Mucosa/metabolism ; Itraconazole/pharmacology ; Liver/metabolism ; Male ; Middle Aged ; Models, Biological ; Phosphatidylinositol 3-Kinase/antagonists & inhibitors ; Pyridines/pharmacokinetics ; Pyrimidines/pharmacokinetics ; Quinidine/pharmacology ; Young Adult
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Cytochrome P-450 CYP3A Inhibitors ; Pyridines ; Pyrimidines ; leniolisib ; Itraconazole (304NUG5GF4) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Quinidine (ITX08688JL)
Language	English
Publishing date	2018-08-31
Publishing country	England
Document type	Clinical Trial ; Journal Article
ZDB-ID	603014-2
ISSN	1099-081X ; 0142-2782
ISSN (online)	1099-081X
ISSN	0142-2782
DOI	10.1002/bdd.2157
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Zs.A 1520: Show issues

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Article: Physiologically based approaches towards the prediction of pharmacokinetics: in vitro-in vivo extrapolation.

De Buck, Stefan S / Mackie, Claire E

Expert opinion on drug metabolism & toxicology

2007 Volume 3, Issue 6, Page(s) 865–878

Abstract: In adapting to the challenge to make more informed selection of compounds for development, the pharmaceutical industry is increasingly embracing the application of mechanism-based models and prediction tools for prediction of pharmacokinetic parameters. ... ...

Abstract	In adapting to the challenge to make more informed selection of compounds for development, the pharmaceutical industry is increasingly embracing the application of mechanism-based models and prediction tools for prediction of pharmacokinetic parameters. This review first outlines the concepts and application of the major physiologically based prediction tools to extrapolate clearance, tissue distribution, and rate and extent of absorption from minimal in vitro or animal in vivo input data. Finally, the ability of these prediction tools, when placed within a generic whole body physiologically based model of pharmacokinetics, to predict plasma concentration-time profiles is briefly discussed.
MeSH term(s)	Algorithms ; Animals ; Drug Industry/methods ; Humans ; Metabolic Clearance Rate ; Metabolic Networks and Pathways/physiology ; Models, Biological ; Pharmaceutical Preparations/metabolism ; Pharmacokinetics ; Tissue Distribution
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2007-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2214462-6
ISSN	1742-5255
ISSN	1742-5255
DOI	10.1517/17425255.3.6.865
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Zs.A 6264: Show issues

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Article ; Online: Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies.

De Buck, Stefan S / Jakab, Annamaria / Boehm, Markus / Bootle, Douglas / Juric, Dejan / Quadt, Cornelia / Goggin, Timothy K

British journal of clinical pharmacology

2014 Volume 78, Issue 3, Page(s) 543–555

Abstract: Aims: The aim was to characterize the population pharmacokinetics of BYL719 in cancer patients and assess the time course of tumour response in relation to drug exposure and dosing schedule.: Methods: Plasma samples and longitudinal tumour size ... ...

Abstract	Aims: The aim was to characterize the population pharmacokinetics of BYL719 in cancer patients and assess the time course of tumour response in relation to drug exposure and dosing schedule. Methods: Plasma samples and longitudinal tumour size measurements were collected from 60 patients with advanced solid malignancies who received oral BYL719 once daily (30-450 mg) or twice daily at 120 mg or 200 mg. Non-linear mixed effect modelling was employed to develop the population pharmacokinetic and pharmacodynamic model. Results: The pharmacokinetics were best described by a one compartment disposition model and transit compartments accounting for the lag time in absorption. The typical population oral clearance and volume of distribution estimates with their between-subject variability (BSV) were 10 l h(-1) (BSV 26%) and 108 l (BSV 28%), respectively. The estimated optimal number of transit compartments was 8.1, with a mean transit time to the absorption compartment of 1.28 h (BSV 32%). The between-occasion variability in the rate and extent of absorption was 46% and 26%, respectively. Tumour growth was modelled using a turnover model characterized by a zero order growth rate of 0.581 cm week(1) and a first order death rate of 0.0123 week(-1) . BYL719 inhibited tumour growth with an IC50 of 100 ng ml(-1) (BSV 154%). Model-based predictions showed potential for additional anti-tumour activity of twice daily dosing at total daily dose below 400 mg, but a loss of efficacy if administered less frequently than once daily. Conclusions: The proposed model provides a valuable approach for planning future clinical studies and for designing optimized dosing regimens with BYL719.
MeSH term(s)	Adult ; Aged ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/pharmacokinetics ; Enzyme Inhibitors/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Models, Biological ; Neoplasms/drug therapy ; Neoplasms/pathology ; Nonlinear Dynamics ; Phosphoinositide-3 Kinase Inhibitors ; Thiazoles/administration & dosage ; Thiazoles/pharmacokinetics ; Thiazoles/therapeutic use ; Tissue Distribution
Chemical Substances	Enzyme Inhibitors ; Phosphoinositide-3 Kinase Inhibitors ; Thiazoles ; Alpelisib (08W5N2C97Q)
Language	English
Publishing date	2014-05-05
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.12378
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Zs.A 1118: Show issues

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Article: Specific antibody modulates absorptive transport and metabolic activation of benzo[a]pyrene across Caco-2 monolayers.

De Buck, Stefan S / Augustijns, Patrick / Muller, Claude P

The Journal of pharmacology and experimental therapeutics

2005 Volume 313, Issue 2, Page(s) 640–646

Abstract: It has been shown that oral anticarcinogen antibodies can decrease intestinal absorption of procarcinogens. So far, no attempts have been made to understand the potential modulatory effect of such antibodies on metabolic activation at mucosal surfaces. ... ...

Abstract	It has been shown that oral anticarcinogen antibodies can decrease intestinal absorption of procarcinogens. So far, no attempts have been made to understand the potential modulatory effect of such antibodies on metabolic activation at mucosal surfaces. Moreover, the influence of naturally induced serosal-specific antibodies on absorptive transport of carcinogens remains unknown. In this study, the prototype food carcinogen benzo[a]pyrene (B[a]P) and a specific monoclonal antibody were used to address these questions in a bicompartmental model of polarized intestinal cells (Caco-2). Apical (i.e., luminal) administration of a 30-fold molar excess antibodies increased about 25-fold recovery of unmetabolized B[a]P, concomitantly with a decrease of 80% in both absorptive transport and formation of phenol metabolites. Interestingly, when metabolism was slowed down by antibodies, cross-reactive antibodies also increased at least 5-fold the extracellular levels of the 7,8-diol-B[a]P, interrupting subsequent activation steps. On the other hand, basolateral antibodies changed by 8-fold the rate of carcinogen appearance in the basolateral compartment, albeit without interfering with the apical cellular uptake or sequestration of either B[a]P or 7,8-diol-B[a]P by apical antibodies. Furthermore, basolateral antibodies reduced exposure of Caco-2 monolayers to B[a]P as demonstrated by a 50% decrease in apical efflux of 3-OH-B[a]P. These data show for the first time that both luminal and serosal antibodies may reduce the carcinogenic process by preventing high local concentrations, which would overload DNA repair mechanisms. This study also sheds light on the relevance of both naturally induced and immunoprophylactic antibodies against polycyclic aromatic hydrocarbon carcinogens.
MeSH term(s)	Absorption/immunology ; Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Neoplasm/pharmacology ; Antibody Specificity ; Benzo(a)pyrene/antagonists & inhibitors ; Benzo(a)pyrene/metabolism ; Biological Transport/immunology ; Biotransformation ; Caco-2 Cells ; Carcinogens/antagonists & inhibitors ; Carcinogens/metabolism ; Epithelium/immunology ; Epithelium/metabolism ; Humans ; Intracellular Space/metabolism ; Mice
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neoplasm ; Carcinogens ; Benzo(a)pyrene (3417WMA06D)
Language	English
Publishing date	2005-05
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.104.081034
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Article: Immunopropylactic approaches against chemical carcinogenesis.

De Buck, Stefan S / Muller, Claude P

Vaccine

2005 Volume 23, Issue 17-18, Page(s) 2403–2406

Abstract: Immunoprophylactic strategies using carcinogen-specific antibodies have so far received little attention. This may be due to experimental difficulties of in vivo chemical carcinogenesis models, which conveniently use excessive doses of carcinogen, which ... ...

Abstract	Immunoprophylactic strategies using carcinogen-specific antibodies have so far received little attention. This may be due to experimental difficulties of in vivo chemical carcinogenesis models, which conveniently use excessive doses of carcinogen, which do not reflect environmental exposure and which cannot be matched by molar equivalents of antibodies. However, more recent studies have now demonstrated that both mucosal and systemic antibodies may afford protection against low doses of environmental carcinogens, at least when stoichiometry between carcinogen and antibody is respected. Mucosal antibodies could decrease both systemic uptake and metabolic activation at the site of entry. Systemic antibodies may change the kinetics of carcinogen metabolism and redistribute carcinogens within the organism. Antibody-mediated redistribution may favor metabolism in less sensitive distal organs and thus result in lower concentrations of adduct-forming species at mucosal surfaces and other sensitive cells. This may be accomplished by avoiding threshold concentrations of carcinogens required for triggering carcinogen-mediated cytochrome P450 induction and tumor promotion. Studies at immunoprophylactic intervention in carcinogenicity are discussed.
MeSH term(s)	Animals ; Antibodies, Neoplasm/metabolism ; Biotransformation ; Carcinogens, Environmental/pharmacokinetics ; Carcinogens, Environmental/toxicity ; Humans ; Models, Immunological ; Neoplasms/chemically induced ; Neoplasms/immunology ; Neoplasms/prevention & control ; Vaccination
Chemical Substances	Antibodies, Neoplasm ; Carcinogens, Environmental
Language	English
Publishing date	2005-03-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2005.01.020
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Zs.A 1930: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Effects of antibodies induced by a conjugate vaccine on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone absorptive transport, metabolism, and proliferation of human lung cells.

De Buck, Stefan S / Schellenberger, Mario T / Ensch, Corinne / Muller, Claude P

International journal of cancer

2010 Volume 127, Issue 3, Page(s) 513–520

Abstract: One of the most abundant and potent lung carcinogen is the nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The monoclonal antibody P9D5 induced with a NNK-conjugate vaccine was used to investigate the ... ...

Abstract	One of the most abundant and potent lung carcinogen is the nicotine-derived tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The monoclonal antibody P9D5 induced with a NNK-conjugate vaccine was used to investigate the ability of NNK-specific antibodies to modulate NNK-induced adverse effects as well as its absorptive transport and metabolism in two lung cancer cell lines (Calu-3 and NCI-H82). Transport experiments in Calu-3 cells with a 50-fold molar excess of apical P9D5 increased the recovery of coadministered apical NNK, with a concomitant decrease in NNK transepithelial transport of more than 50% compared to controls. In contrast, basolateral P9D5 did neither influence transepithelial transport of NNK nor its disappearance from the apical compartment. Calu-3 cells were also found to reduce NNK to NNAL and a 65-fold molar excess of NNK-specific antibody inhibited this metabolic conversion by 46 and 54% compared to irrelevant control antibody after 48 and 72 hr, respectively. The biological relevance of NNK redistribution by antibody was demonstrated by reversion of NNK-induced cell proliferation in NCI-H82 cells. Repartitioning of tobacco carcinogens by antibody may reduce their early effective peak concentrations in susceptible target organs and thus relieve overloaded local DNA repair mechanisms and diminish carcinogen-induced cell proliferation. These in vitro data therefore suggest that a prophylactic antibody response may be associated with a reduced risk of cancer.
MeSH term(s)	Antibodies, Monoclonal/immunology ; Biological Transport ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Lung/cytology ; Lung/immunology ; Lung Neoplasms/pathology ; Nitrosamines/immunology ; Nitrosamines/metabolism ; Nitrosamines/pharmacokinetics ; Vaccines/immunology
Chemical Substances	Antibodies, Monoclonal ; Nitrosamines ; Vaccines ; 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (7S395EDO61)
Language	English
Publishing date	2010-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.25073
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Zs.A 478: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Modulation of the metabolism and adverse effects of benzo[a]pyrene by a specific antibody: a novel host factor in environmental carcinogenesis?

De Buck, Stefan S / Bouche, Fabienne B / Brandenburger, Annick / Muller, Claude P

Carcinogenesis

2005 Volume 26, Issue 4, Page(s) 835–844

Abstract: The influence of specific antibodies on molecular and cellular mechanisms of activation, detoxification and biological activity of the ubiquitous carcinogen benzo[a]pyrene (B[a]P) was investigated using a monoclonal antibody. The antibody was shown to ... ...

Abstract	The influence of specific antibodies on molecular and cellular mechanisms of activation, detoxification and biological activity of the ubiquitous carcinogen benzo[a]pyrene (B[a]P) was investigated using a monoclonal antibody. The antibody was shown to decrease cellular uptake and metabolic activation of B[a]P as demonstrated by higher recovery of unmetabolized B[a]P and decreased formation of end-point phenol metabolites in two types of target cells. Furthermore, strong antibody reactivity with 7,8-diol-B[a]P provided a second chance for interrupting metabolic activation by sequestration of this intermediate metabolite in the extracellular space. The biological relevance of B[a]P and 7,8-diol-B[a]P redistribution by antibody was demonstrated by reversion of B[a]P-induced inhibition of proliferation of human peripheral blood lymphocytes and by inhibition of CYP 1A1 induction in HepG2 cells. Remarkably, the antibody was still protective against B[a]P-induced immunotoxicity even after delayed addition, suggesting a more important role of metabolites in immunotoxicity than has been appreciated so far. Although B[a]P is activated to 7,8-diol-B[a]P in the same cells that are inhibited by this metabolite, the antibody completely restored lymphocyte proliferation indicating that extracellular trapping of the 7,8-diol-B[a]P is biologically highly effective. Thus, repartitioning of both B[a]P and its metabolites by the antibody may reduce their effective concentration in susceptible target organs and therefore relieve overloaded DNA repair mechanisms and inhibit carcinogen-induced P450 induction. These in vitro data also suggest that a natural or prophylactic antibody response against carcinogens may be associated with a reduced risk of cancer.
MeSH term(s)	Alkylation/drug effects ; Animals ; Antibodies, Monoclonal/pharmacology ; Benzo(a)pyrene/metabolism ; Carcinogens/adverse effects ; Carcinogens/metabolism ; Carcinoma, Hepatocellular/immunology ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation/drug effects ; Cytochrome P-450 CYP1A1/antagonists & inhibitors ; Cytochrome P-450 CYP1A1/immunology ; Cytochrome P-450 CYP1A1/metabolism ; DNA Adducts ; Dihydroxydihydrobenzopyrenes/adverse effects ; Dihydroxydihydrobenzopyrenes/metabolism ; Female ; Humans ; Liver Neoplasms/immunology ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Lymphocytes/drug effects ; Microsomes, Liver/drug effects ; Rats ; Rats, Wistar
Chemical Substances	Antibodies, Monoclonal ; Carcinogens ; DNA Adducts ; Dihydroxydihydrobenzopyrenes ; benzo(a)pyrene 7,8-dihydrodiol (13345-25-0) ; Benzo(a)pyrene (3417WMA06D) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1)
Language	English
Publishing date	2005-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603134-1
ISSN	1460-2180 ; 0143-3334
ISSN (online)	1460-2180
ISSN	0143-3334
DOI	10.1093/carcin/bgi010
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