Mathematical model of uptake and metabolism of arsenic(III) in human hepatocytes - Incorporation of cellular antioxidant response and threshold-dependent behavior.
BACKGROUND
Arsenic is an environmental pollutant, potent human toxicant, and oxidative stress agent with a multiplicity of health effects associated with both acute and chronic exposures. A semi-mechanistic cellular-level toxicokinetic (TK) model was developed in order to describe the uptake, biotransformation and clearance of arsenical species in human hepatocytes. Notable features of this model are the incorporation of arsenic-glutathione complex formation and a "switch-like" formulation to describe the antioxidant response of hepatocytes to arsenic exposure.


RESULTS
The cellular-level TK model applies mass action kinetics in order to predict the concentrations of trivalent and pentavalent arsenicals in hepatocytes. The model simulates uptake of arsenite (iAsIII) via aquaporin isozymes 9 (AQP9s), glutathione (GSH) conjugation, methylation by arsenic methyltransferase (AS3MT), efflux through multidrug resistant proteins (MRPs) and the induced antioxidant response via thioredoxin reductase (TR) activity. The model was parameterized by optimization of model estimates for arsenite (iAsIII), monomethylated (MMA) and dimethylated (DMA) arsenicals concentrations with time-course experimental data in human hepatocytes for a time span of 48 hours, and dose-response data at 24 hours for a range of arsenite concentrations from 0.1 to 10 μM. Global sensitivity analysis of the model showed that at low doses the transport parameters had a dominant role, whereas at higher doses the biotransformation parameters were the most significant. A parametric comparison of the TK model with an analogous model developed for rat hepatocytes from the literature demonstrated that the biotransformation of arsenite (e.g. GSH conjugation) has a large role in explaining the variation in methylation between rats and humans.


CONCLUSIONS
The cellular-level TK model captures the temporal modes of arsenical accumulation in human hepatocytes. It highlighted the key biological processes that influence arsenic metabolism by explicitly modelling the metabolic network of GSH-adducts formation. The parametric comparison with the TK model developed for rats suggests that the variability in GSH conjugation could have an important role in inter-species variability of arsenical methylation. The TK model can be incorporated into larger-scale physiologically based toxicokinetic (PBTK) models of arsenic for improving the estimates of PBTK model parameters.
Environmental and Occupational Health Sciences Institute (EOHSI), a joint institute of UMDNJ-Robert Wood Johnson Medical School and Rutgers University, 170 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
Spyros K
SK
Stamatelos
Christopher J
CJ
Brinkerhoff
Sastry S
SS
Isukapalli
Panos G
PG
Georgopoulos
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001151:Arsenic / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D001692:Biological Transport; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D051381:Rats
D000975:Antioxidants; D004785:Environmental Pollutants; D001151:Arsenic
Toxicol Sci. 2009 Feb;107(2):309-11
19074764
PLoS Comput Biol. 2007 Oct;3(10):1871-78
17922568
Toxicol Appl Pharmacol. 2007 Aug 1;222(3):281-8
17118416
Toxicol Appl Pharmacol. 2004 Dec 1;201(2):166-77
15541756
Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1106-11
16415156
Exp Biol Med (Maywood). 2007 Jan;232(1):3-13
17202581
Mutat Res. 2003 Dec 10;533(1-2):37-65
14643412
Crit Rev Toxicol. 2006 Feb;36(2):99-133
16736939
Chem Res Toxicol. 2006 Jul;19(7):894-8
16841956
Biochem Biophys Res Commun. 2006 Dec 15;351(2):424-30
17064664
Toxicol Appl Pharmacol. 2009 Mar 15;235(3):338-50
19168087
Environ Toxicol Pharmacol. 2007 Jan;23(1):115-20
21783745
Toxicol Appl Pharmacol. 2004 Aug 1;198(3):319-26
15276411
Crit Rev Toxicol. 2009;39(4):271-98
19235533
Regul Toxicol Pharmacol. 2008 Feb;50(1):129-43
18077066
J Cell Biol. 1991 Oct;115(2):485-93
1655806
Free Radic Biol Med. 2004 Nov 15;37(10):1511-26
15477003
Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10840-5
16829571
Drug Metab Dispos. 2008 May;36(5):971-9
18256204
Regul Toxicol Pharmacol. 1999 Apr;29(2 Pt 1):128-41
10341143
Chem Res Toxicol. 2006 Aug;19(8):1010-8
16918239
Carcinogenesis. 2003 May;24(5):967-74
12771042
Indian J Med Res. 2008 Oct;128(4):436-47
19106439
Chem Res Toxicol. 2001 Mar;14(3):305-11
11258980
J Biol Chem. 1970 Nov 10;245(21):5788-99
5472372
Toxicol Appl Pharmacol. 2007 Aug 1;222(3):365-73
17397889
Biochem J. 2006 May 1;395(3):599-609
16426233
J Inorg Biochem. 2008 Mar;102(3):532-9
18164070
Teratog Carcinog Mutagen. 1999;19(6):385-402
10587409
J Pharmacokinet Pharmacodyn. 2002 Jun;29(3):207-34
12449496
J Pharmacokinet Pharmacodyn. 2008 Feb;35(1):31-68
17943421
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6053-8
11972053
Toxicol Sci. 2002 Jun;67(2):159-72
12011475
Arch Toxicol. 2005 Apr;79(4):183-91
15526190
Toxicol Appl Pharmacol. 1997 May;144(1):135-44
9169077
Toxicol Sci. 2009 Feb;107(2):416-26
18779381
Chem Res Toxicol. 2004 Mar;17(3):404-9
15025511
FEBS Lett. 2006 Mar 20;580(7):1771-4
16516206
J Biol Chem. 2004 Jul 30;279(31):32700-8
15161912
Arch Toxicol. 1985 Jun;57(2):119-24
4026570
Toxicol Appl Pharmacol. 1996 Oct;140(2):471-86
8887465
Toxicol Sci. 2004 Dec;82(2):478-87
15342953
Toxicol Sci. 2005 Sep;87(1):46-56
15947026
Chem Res Toxicol. 2004 Feb;17(2):243-9
14967012
J Pharmacol Exp Ther. 2009 Jul;330(1):169-78
19386792
Am J Physiol. 1999 Nov;277(5):F685-96
10564231
J Biol Chem. 2000 Oct 27;275(43):33404-8
10938093
Chem Res Toxicol. 1999 Jul;12(7):560-5
10409394
Arch Toxicol. 2010 Jan;84(1):3-16
20020104
Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):385-94
15706085
J Mol Biol. 1965 May;12:88-118
14343300
Mol Carcinog. 2009 Feb;48(2):91-104
18618599
Science. 1998 May 8;280(5365):895-8
9572732
Chem Res Toxicol. 2008 Sep;21(9):1760-9
18597498
J Physiol. 1952 Aug;117(4):500-44
12991237
Environ Health Perspect. 2002 Dec;110 Suppl 6:971-8
12634127
Curr Opin Cell Biol. 2003 Apr;15(2):221-31
12648679
J Biol Chem. 2006 Aug 18;281(33):23620-31
16785233
Toxicol Appl Pharmacol. 2004 Dec 1;201(2):156-65
15541755
Toxicol In Vitro. 2009 Mar;23(2):209-16
19100828
Toxicol Appl Pharmacol. 2008 Aug 1;230(3):383-9
18417180
J Biol Chem. 2006 Mar 17;281(11):7364-73
16407288