CYP1A2 and NAT2 phenotyping and 3-aminobiphenyl and 4-aminobiphenyl hemoglobin adduct levels in smokers and non-smokers.

2.50
Hdl Handle:
http://hdl.handle.net/10146/57213
Title:
CYP1A2 and NAT2 phenotyping and 3-aminobiphenyl and 4-aminobiphenyl hemoglobin adduct levels in smokers and non-smokers.
Authors:
Sarkar, Mohamadi; Stabbert, Regina; Kinser, Robin D.; Oey, Jan; Rustemeier, Klaus; von Holt, Klaus; Schepers, Georg; Walk, Roger A.; Roethig, Hans J.
Abstract:
Some aromatic amines are considered to be putative bladder carcinogens. Hemoglobin (Hb) adducts of 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP) have been used as biomarkers of exposure to aromatic amines from cigarette smoke. One of the goals of this study was to determine intra- and inter-individual variability in 3-ABP and 4-ABP Hb adducts and to explore the predictability of ABP Hb adduct levels based on caffeine phenotyping. The study was conducted in adult smokers (S, n = 65) and non-smokers (NS, n = 65). The subjects were phenotyped for CYP1A2 and NAT2 using urinary caffeine metabolites. Blood samples were collected twice within 6 weeks and adducts measured by GC/MS. The levels of 4-ABP Hb adducts were significantly (p < 0.0001) greater in S (34.5 +/- 21.06 pg/g Hb) compared to NS (6.3 +/- 3.02 pg/g Hb). The levels of 3-ABP Hb adducts were below the limit of quantification (BLOQ) in most (82%) of the NS and about 10-fold lower in S (3.6 +/- 3.29 pg/g Hb) compared to 4-ABP Hb adducts. No differences were observed in the adduct levels between weeks 1 and 6 in the smokers, suggesting that a single sample would be adequate to monitor cigarette smoke exposure. The regression model developed with CYP1A2, NAT2 phenotype and number of cigarettes smoked (NCIG) accounted for 47% of the variability in 3-ABP adducts, whereas 32% variability in 4-ABP adducts was accounted by CYP1A2 and NCIG. The ratio of 4-ABP Hb adducts in adult S:NS was approximately 5:1, whereas 3-ABP Hb adducts levels were BLOQ in some S, exhibited large interindividual variability ( approximately 91% compared to 57% for 4-ABP Hb) and poor dose response relationship. Therefore, 4-ABP Hb adduct levels may be a more useful biomarker of aminobiphenyl exposure from cigarette smoke.
Citation:
Toxicol. Appl. Pharmacol. 2006, 213 (3):198-206
Journal:
Toxicology and applied pharmacology
Issue Date:
15-Jun-2006
URI:
http://hdl.handle.net/10146/57213
DOI:
10.1016/j.taap.2005.11.003
PubMed ID:
16405939
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4J021H3-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=0dfb41d0b675eaffef446561954cd6e3
Type:
Article
Language:
en
Description:
Biomarkers of exposure & effect:: validationBiomarker: 3-ABP and 4-ABP Hb adductExposure/effect represented: tar Study type (in vitro, animals, humans): humansStudy design (if human): case-controlStudy size (if human): 65 healthy adult smokers (37 females and 28 males) and 65 healthy nonsmokers (35 females and 30 males)Mode of exposure (if in vivo) (acute, chronic, root of exposure): every day smoking for 12 monthsTissue/biological material/sample size: 10ml peripheral blood Method of analysis: ref.(Kutzer, C., Branner, B., Zwickenpflug, W., Richter, E., 1997. Simultaneous solid-phase extraction and gas chromatographic-mass spectrometric determination of hemoglobin adducts from tobacco-specific nitrosamines and aromatic amines. J. Chromatogr. Sci. 35, 1-6.) , GC-MS Sensitivity (LOD): The lower limit of quantification (LLOQ) was 0.5 pg/g Hb for both 3-ABP and 4-ABP Hb adducts with linearity demonstrable up to 500 pg/g Hb (upper limit of quantification, ULOQ).Accuracy: for 3-ABP 4.7%-7.7%, for 4-ABP is 7.3%-2.5%Interday precision: : for 4-ABP is 5%-16.4%Dose-response: Both the 3-ABP and 4-ABP Hb adducts were significantly higher ( p b 0.05) in smokers compared to non-smokersThere was a significant difference (p b 0.001) in ABP adduct levels between those subjects smoking b20 cigarettes/day (3-ABP Hb = 2.76 ± 2.47 and 4- ABP Hb = 28.30 ± 19.70 pg/g Hb; n = 39) and ?20 cigarettes/ day (3-ABP Hb = 5.56 ± 3.80 and 4-ABP Hb = 46.30 ± 18.70 pg/g Hb; n = 22).the levels of 4-ABP Hb adducts were significantly lower in females, compared to male smokers, during week 1 ( p b 0.05), but not during week 6The 4-ABP Hb adduct levels in smokers were similar between week 1 and week 6 in males but significantly lower ( p b 0.05) in females during week 1 compared to week 6. There was a significant linear correlation between 3-ABP and 4-ABP Hb adducts in smokers ( p b 0.0001, r2 = 0.62).Stability in stored sample: unprocessed samples can be stored at room 4temperature for up to 24 h, processed samples at ?20 °C for up to 12.5 days, without any significant degradation. The stability of 3-ABP and 4-ABP Hb adducts in blood was confirmed for a total of 4 freeze/thaw cycles. KEYWORDS CLASSIFICATION: Adult;Aged;Aminobiphenyl Compounds;Arylamine N-Acetyltransferase;biomarkers of exposure & effect: field studies;biomarkers of individual susceptibility: field studies;Biological Markers;Carcinogens;Cytochrome P-450 CYP1A2;Female;Hemoglobins;Humans;metabolism;Male;Middle Aged;Phenotype;Protein Binding;Smoking.
ISSN:
0041-008X
Appears in Collections:
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Full metadata record

DC FieldValue Language
dc.contributor.authorSarkar, Mohamadi-
dc.contributor.authorStabbert, Regina-
dc.contributor.authorKinser, Robin D.-
dc.contributor.authorOey, Jan-
dc.contributor.authorRustemeier, Klaus-
dc.contributor.authorvon Holt, Klaus-
dc.contributor.authorSchepers, Georg-
dc.contributor.authorWalk, Roger A.-
dc.contributor.authorRoethig, Hans J.-
dc.date.accessioned2009-03-26T08:32:40Z-
dc.date.available2009-03-26T08:32:40Z-
dc.date.issued2006-06-15-
dc.identifier.citationToxicol. Appl. Pharmacol. 2006, 213 (3):198-206en
dc.identifier.issn0041-008X-
dc.identifier.pmid16405939-
dc.identifier.doi10.1016/j.taap.2005.11.003-
dc.identifier.urihttp://hdl.handle.net/10146/57213-
dc.descriptionBiomarkers of exposure & effect:: validationBiomarker: 3-ABP and 4-ABP Hb adductExposure/effect represented: tar Study type (in vitro, animals, humans): humansStudy design (if human): case-controlStudy size (if human): 65 healthy adult smokers (37 females and 28 males) and 65 healthy nonsmokers (35 females and 30 males)Mode of exposure (if in vivo) (acute, chronic, root of exposure): every day smoking for 12 monthsTissue/biological material/sample size: 10ml peripheral blood Method of analysis: ref.(Kutzer, C., Branner, B., Zwickenpflug, W., Richter, E., 1997. Simultaneous solid-phase extraction and gas chromatographic-mass spectrometric determination of hemoglobin adducts from tobacco-specific nitrosamines and aromatic amines. J. Chromatogr. Sci. 35, 1-6.) , GC-MS Sensitivity (LOD): The lower limit of quantification (LLOQ) was 0.5 pg/g Hb for both 3-ABP and 4-ABP Hb adducts with linearity demonstrable up to 500 pg/g Hb (upper limit of quantification, ULOQ).Accuracy: for 3-ABP 4.7%-7.7%, for 4-ABP is 7.3%-2.5%Interday precision: : for 4-ABP is 5%-16.4%Dose-response: Both the 3-ABP and 4-ABP Hb adducts were significantly higher ( p b 0.05) in smokers compared to non-smokersThere was a significant difference (p b 0.001) in ABP adduct levels between those subjects smoking b20 cigarettes/day (3-ABP Hb = 2.76 ± 2.47 and 4- ABP Hb = 28.30 ± 19.70 pg/g Hb; n = 39) and ?20 cigarettes/ day (3-ABP Hb = 5.56 ± 3.80 and 4-ABP Hb = 46.30 ± 18.70 pg/g Hb; n = 22).the levels of 4-ABP Hb adducts were significantly lower in females, compared to male smokers, during week 1 ( p b 0.05), but not during week 6The 4-ABP Hb adduct levels in smokers were similar between week 1 and week 6 in males but significantly lower ( p b 0.05) in females during week 1 compared to week 6. There was a significant linear correlation between 3-ABP and 4-ABP Hb adducts in smokers ( p b 0.0001, r2 = 0.62).Stability in stored sample: unprocessed samples can be stored at room 4temperature for up to 24 h, processed samples at ?20 °C for up to 12.5 days, without any significant degradation. The stability of 3-ABP and 4-ABP Hb adducts in blood was confirmed for a total of 4 freeze/thaw cycles. KEYWORDS CLASSIFICATION: Adult;Aged;Aminobiphenyl Compounds;Arylamine N-Acetyltransferase;biomarkers of exposure & effect: field studies;biomarkers of individual susceptibility: field studies;Biological Markers;Carcinogens;Cytochrome P-450 CYP1A2;Female;Hemoglobins;Humans;metabolism;Male;Middle Aged;Phenotype;Protein Binding;Smoking.en
dc.description.abstractSome aromatic amines are considered to be putative bladder carcinogens. Hemoglobin (Hb) adducts of 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP) have been used as biomarkers of exposure to aromatic amines from cigarette smoke. One of the goals of this study was to determine intra- and inter-individual variability in 3-ABP and 4-ABP Hb adducts and to explore the predictability of ABP Hb adduct levels based on caffeine phenotyping. The study was conducted in adult smokers (S, n = 65) and non-smokers (NS, n = 65). The subjects were phenotyped for CYP1A2 and NAT2 using urinary caffeine metabolites. Blood samples were collected twice within 6 weeks and adducts measured by GC/MS. The levels of 4-ABP Hb adducts were significantly (p < 0.0001) greater in S (34.5 +/- 21.06 pg/g Hb) compared to NS (6.3 +/- 3.02 pg/g Hb). The levels of 3-ABP Hb adducts were below the limit of quantification (BLOQ) in most (82%) of the NS and about 10-fold lower in S (3.6 +/- 3.29 pg/g Hb) compared to 4-ABP Hb adducts. No differences were observed in the adduct levels between weeks 1 and 6 in the smokers, suggesting that a single sample would be adequate to monitor cigarette smoke exposure. The regression model developed with CYP1A2, NAT2 phenotype and number of cigarettes smoked (NCIG) accounted for 47% of the variability in 3-ABP adducts, whereas 32% variability in 4-ABP adducts was accounted by CYP1A2 and NCIG. The ratio of 4-ABP Hb adducts in adult S:NS was approximately 5:1, whereas 3-ABP Hb adducts levels were BLOQ in some S, exhibited large interindividual variability ( approximately 91% compared to 57% for 4-ABP Hb) and poor dose response relationship. Therefore, 4-ABP Hb adduct levels may be a more useful biomarker of aminobiphenyl exposure from cigarette smoke.en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4J021H3-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=0dfb41d0b675eaffef446561954cd6e3en
dc.subjectAromatic aminesen
dc.subject3-Aminobiphenylen
dc.subject4-Aminobiphenylen
dc.subjectBiomarkersen
dc.subjectBladder canceren
dc.subjectCigarette smokeen
dc.subjectCytochrome P4501A2en
dc.subjectExposure studyen
dc.subjectHemoglobin adductsen
dc.subjectPhenotypeen
dc.subjectN-acetyltransferaseen
dc.subjectPolymorphismen
dc.subjectTobacco smoke carcinogensen
dc.subjectRisken
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAminobiphenyl Compounds-
dc.subject.meshArylamine N-Acetyltransferase-
dc.subject.meshBiological Markers-
dc.subject.meshCarcinogens-
dc.subject.meshCytochrome P-450 CYP1A2-
dc.subject.meshFemale-
dc.subject.meshHemoglobins-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshPhenotype-
dc.subject.meshProtein Binding-
dc.subject.meshSmoking-
dc.titleCYP1A2 and NAT2 phenotyping and 3-aminobiphenyl and 4-aminobiphenyl hemoglobin adduct levels in smokers and non-smokers.en
dc.typeArticleen
dc.identifier.journalToxicology and applied pharmacologyen

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