Quantitative analysis and chronic dosimetry of the aflatoxin B1 plasma albumin adduct Lys-AFB1 in rats by isotope dilution mass spectrometry

Peter F. Scholl, Les McCoy, Thomas W. Kensler, John D. Groopman

Research output: Contribution to journalArticlepeer-review

Abstract

Aflatoxin B1 (AFB1) is a major risk factor in the pathogenesis of liver cancer in Asia and sub-Saharan Africa. Biomarkers reflecting exposure will facilitate disease risk assessment and the efficacy of protective interventions in these populations. The Lys-AFB1 adduct in plasma albumin is a candidate biomarker for this role. Although aflatoxin albumin adducts are most frequently measured in epidemiological studies using an enzyme-linked immunosorbent assay, a more specific and 10-fold more sensitive isotopic dilution mass spectrometric assay for Lys-AFB1 has recently become available. Here, the dosimetry of chronically administered AFB 1 at lower doses than have been previously studied was explored using this assay. AFB1 was administered to rats for nine consecutive days at eight dose levels ranging from 50 pg to 55 μg/kg body wt. Plasma samples were enzymatically digested and processed by solid phase extraction. Lys-AFB1 was isolated by HPLC and detected via selected reaction monitoring. The dose-response relationship was linear-quadratic exhibiting upward curvature at higher doses. The adduct yield [(pg Lys-AFB1/mg albumin)/(μg AFB1/kg body wt)] increased nonlinearly with the dose by 6-fold between the 0.05 and 55 μg AFB1/kg body wt groups and exhibited the onset of saturation in the highest dose group where the adduct yield was approximately 2%. Incomplete knowledge of the timing of exposure and the complexity of the underlying biology confound the precise determination of prior AFB1 exposures in humans; however, the dosimetry of AFB 1 observed in chronically dosed rats conceptually suggests that measurements in humans may underestimate exposure if a constant fraction of the AFB1 dose, approximately 2%, is assumed to be converted to Lys-AFB1 without regard to the dose.

Original languageEnglish (US)
Pages (from-to)44-49
Number of pages6
JournalChemical research in toxicology
Volume19
Issue number1
DOIs
StatePublished - Jan 2006

ASJC Scopus subject areas

  • Toxicology

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