Polycyclic Aromatic Hydrocarbons (PAHs): The Role of Human Transport Systems in the Fate and Toxic Effects

Slobodan RP

Slobodan RP

Volume6-Issue11
Dates: Received: 2025-11-03 | Accepted: 2025-11-26 | Published: 2025-11-27
Pages: 1723-1734

Abstract

Presented are the results of the analysis of the published data on the interaction of Polycyclic Aromatic Hydrocarbons (PAHs), known carcinogenic compounds, and their toxic metabolites, with human transporters. The results of the study show that¸ the compounds interact with human transporters as substrates (with 44% of the data), as inducers (with 24% of the data), and as inhibitors (with 32% of the data). PAH compounds metabolites are preferentially transported in the form of the highly polar glucuronides (Glu-conjugates), potentially toxic sulfate-conjugates (Sul-conjugates), and glutathione conjugates (mercapturic acids). Glucuronides and sulfate-conjugates are formed in reactions with OH-groups of the PAH metabolites, and glutathione conjugates react with the toxic epoxide metabolites, being excreted as mecapturic acids. The analysis of the published literature also shows major participation of hOAT transporters (33% of the reactions), MDR1 (P-gp), participate with 21%, and MRP transporters with 18%. The results obtained for the example PAHs and the metabolites are discussed, referring to their application, distribution, excretion, and toxicity to humans. The results also indicate that more research is needed on the transporters' role in the toxicity and fate of PAHs and metabolites in humans.

FullText HTML FullText PDF DOI: 10.37871/jbres2225

Certificate of Publication

Copyright

How to cite this article

Slobodan RP. Polycyclic Aromatic Hydrocarbons (PAHs): The Role of Human Transport Systems in the Fate and Toxic Effects. J Biomed Res Environ Sci. 2025 Nov 27; 6(11): 1723-1734. doi: 10.37871/ jbres2225, Article ID: JBRES2225, Available at: https://www.jelsciences.com/articles/jbres2225.pdf

Subject area(s)

Environmental Impacts

Environmental Contamination

Ecotoxicology

References

Feng Y, Li Zhuo, Wenjing Li, Polycyclic Aromatic Hydrocarbons (PAHs): Environmental persistence and human health risks. Natural Product Communications. 2025;20(1):1-8. doi: 10.1177/1934578X241311451.
Rendic S, Guengerich FP. Contributions of human enzymes in carcinogen metabolism. Chem Res Toxicol. 2012 Jul 16;25(7):1316-83. doi: 10.1021/tx300132k. Epub 2012 May 10. PMID: 22531028; PMCID: PMC3398241.
Rendic SP, Guengerich FP. Development and Uses of Offline and Web-Searchable Metabolism Databases - The Case of Benzo[a]pyrene. Curr Drug Metab. 2018;19(1):3-46. doi: 10.2174/1389200219666171207123939. PMID: 29219051; PMCID: PMC5886801.
Guengerich FP, Rendic S. Update information on drug metabolism systems--2009, part I. Curr Drug Metab. 2010 Jan;11(1):1-3. doi: 10.2174/138920010791110908. PMID: 20307256; PMCID: PMC4755716.
Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 2005 May 1;204(3):216-37. doi: 10.1016/j.taap.2004.10.012. PMID: 15845415.
Rendic S, Guengerich FP. Update information on drug metabolism systems--2009, part II: summary of information on the effects of diseases and environmental factors on human cytochrome P450 (CYP) enzymes and transporters. Curr Drug Metab. 2010 Jan;11(1):4-84. doi: 10.2174/138920010791110917. PMID: 20302566; PMCID: PMC4167379.
Robinson JR, Felton JS, Levitt RC, Thorgeirsson SS, Nebert DW. Relationship between "aromatic hydrocarbon responsiveness" and the survival times in mice treated with various drugs and environmental compounds. Mol Pharmacol. 1975 Nov;11(6):850-65. PMID: 54870.
Mathiesen L, Rytting E, Mose T, Knudsen LE. Transport of benzo[alpha]pyrene in the dually perfused human placenta perfusion model: effect of albumin in the perfusion medium. Basic Clin Pharmacol Toxicol. 2009 Sep;105(3):181-7. doi: 10.1111/j.1742-7843.2009.00431.x. Epub 2009 Jun 5. PMID: 19508462.
Karttunen V, Myllynen P, Prochazka G, Pelkonen O, Segerbäck D, Vähäkangas K. Placental transfer and DNA binding of benzo(a)pyrene in human placental perfusion. Toxicol Lett. 2010 Aug 16;197(2):75-81. doi: 10.1016/j.toxlet.2010.04.028. Epub 2010 May 11. PMID: 20466050.
Bakhiya N, Stephani M, Bahn A, Ugele B, Seidel A, Burckhardt G, Glatt H. Uptake of chemically reactive, DNA-damaging sulfuric acid esters into renal cells by human organic anion transporters. J Am Soc Nephrol. 2006 May;17(5):1414-21. doi: 10.1681/ASN.2005080801. Epub 2006 Apr 5. PMID: 16597690.
Geyer J, Döring B, Meerkamp K, Ugele B, Bakhiya N, Fernandes CF, Godoy JR, Glatt H, Petzinger E. Cloning and functional characterization of human sodium-dependent organic anion transporter (SLC10A6). J Biol Chem. 2007 Jul 6;282(27):19728-41. doi: 10.1074/jbc.M702663200. Epub 2007 May 9. PMID: 17491011.
Phang JM, Poore CM, Lopaczynska J, Yeh GC. Flavonol-stimulated efflux of 7,12-dimethylbenz(a)anthracene in multidrug-resistant breast cancer cells. Cancer Res. 1993 Dec 15;53(24):5977-81. PMID: 7903198.
Chavan H, Krishnamurthy P. Polycyclic aromatic hydrocarbons (PAHs) mediate transcriptional activation of the ATP binding cassette transporter ABCB6 gene via the aryl hydrocarbon receptor (AhR). J Biol Chem. 2012 Sep 14;287(38):32054-68. doi: 10.1074/jbc.M112.371476. Epub 2012 Jul 2. PMID: 22761424; PMCID: PMC3442536.
Yeh GC, Lopaczynska J, Poore CM, Phang JM. A new functional role for P-glycoprotein: efflux pump for benzo(alpha)pyrene in human breast cancer MCF-7 cells. Cancer Res. 1992 Dec 1;52(23):6692-5. PMID: 1358437.
Sugihara N, Toyama K, Okamoto T, Kadowaki M, Terao K, Furuno K. Effects of benzo(e)pyrene and benzo(a)pyrene on P-glycoprotein-mediated transport in Caco-2 cell monolayer: a comparative approach. Toxicol In Vitro. 2007 Aug;21(5):827-34. doi: 10.1016/j.tiv.2007.02.005. Epub 2007 Feb 24. PMID: 17408918.
Lampen A, Ebert B, Stumkat L, Jacob J, Seidel A. Induction of gene expression of xenobiotic metabolism enzymes and ABC-transport proteins by PAH and a reconstituted PAH mixture in human Caco-2 cells. Biochim Biophys Acta. 2004 Nov 24;1681(1):38-46. doi: 10.1016/j.bbaexp.2004.09.010. PMID: 15566942.
Sugihara N, Toyama K, Michihara A, Akasaki K, Tsuji H, Furuno K. Effect of benzo[a]pyrene on P-glycoprotein-mediated transport in Caco-2 cell monolayer. Toxicology. 2006 Jun 1;223(1-2):156-65. doi: 10.1016/j.tox.2006.03.011. Epub 2006 Mar 28. PMID: 16647797.
Schuetz EG, Yasuda K, Arimori K, Schuetz JD. Human MDR1 and mouse mdr1a P-glycoprotein alter the cellular retention and disposition of erythromycin, but not of retinoic acid or benzo(a)pyrene. Arch Biochem Biophys. 1998 Feb 15;350(2):340-7. doi: 10.1006/abbi.1997.0537. PMID: 9473310.
Ebert B, Seidel A, Lampen A. Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis. 2005 Oct;26(10):1754-63. doi: 10.1093/carcin/bgi139. Epub 2005 May 25. PMID: 15917307.
Buesen R, Mock M, Seidel A, Jacob J, Lampen A. Interaction between metabolism and transport of benzo[a]pyrene and its metabolites in enterocytes. Toxicol Appl Pharmacol. 2002 Sep 15;183(3):168-78. doi: 10.1006/taap.2002.9484. PMID: 12383708.
Ebert B, Seidel A, Lampen A. Phytochemicals induce breast cancer resistance protein in Caco-2 cells and enhance the transport of benzo[a]pyrene-3-sulfate. Toxicol Sci. 2007 Apr;96(2):227-36. doi: 10.1093/toxsci/kfl147. Epub 2006 Oct 31. PMID: 17077187.
Hessel S, Lampen A. All-trans retinoic acid enhances the transport of phase II metabolites of benzo[a]pyrene by inducing the Breast Cancer Resistance Protein expression in Caco-2 cells. Toxicol Lett. 2010 Aug 16;197(2):151-5. doi: 10.1016/j.toxlet.2010.05.018. Epub 2010 Jun 1. PMID: 20562004.
Zhou SF, Wang LL, Di YM, Xue CC, Duan W, Li CG, Li Y. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem. 2008;15(20):1981-2039. doi: 10.2174/092986708785132870. PMID: 18691054.
Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000 Feb 11;275(6):4507-12. doi: 10.1074/jbc.275.6.4507. PMID: 10660625.
Hessel S, John A, Seidel A, Lampen A. Multidrug resistance-associated proteins are involved in the transport of the glutathione conjugates of the ultimate carcinogen of benzo[a]pyrene in human Caco-2 cells. Arch Toxicol. 2013 Feb;87(2):269-80. doi: 10.1007/s00204-012-0917-0. Epub 2012 Aug 17. PMID: 22899102.
Buesen R, Mock M, Nau H, Seidel A, Jacob J, Lampen A. Human intestinal Caco-2 cells display active transport of benzo[a]pyrene metabolites. Chem Biol Interact. 2003 Jan 6;142(3):201-21. doi: 10.1016/s0009-2797(02)00076-5. PMID: 12453661.
Hessel S, Lampen A, Seidel A. Polycyclic aromatic hydrocarbons in food--efflux of the conjugated biomarker 1-hydroxypyrene is mediated by Breast Cancer Resistance Protein (ABCG2) in human intestinal Caco-2 cells. Food Chem Toxicol. 2013 Dec;62:797-804. doi: 10.1016/j.fct.2013.10.007. Epub 2013 Oct 16. PMID: 24140465.
Järvinen E, Troberg J, Kidron H, Finel M. Selectivity in the Efflux of Glucuronides by Human Transporters: MRP4 Is Highly Active toward 4-Methylumbelliferone and 1-Naphthol Glucuronides, while MRP3 Exhibits Stereoselective Propranolol Glucuronide Transport. Mol Pharm. 2017 Oct 2;14(10):3299-3311. doi: 10.1021/acs.molpharmaceut.7b00366. Epub 2017 Sep 13. PMID: 28850245.
Bakhiya N, Batke M, Laake J, Monien BH, Frank H, Seidel A, Engst W, Glatt H. Directing role of organic anion transporters in the excretion of mercapturic acids of alkylated polycyclic aromatic hydrocarbons. Drug Metab Dispos. 2007 Oct;35(10):1824-31. doi: 10.1124/dmd.107.016964. Epub 2007 Jul 16. PMID: 17639024.
Gant TW, Silverman JA, Bisgaard HC, Burt RK, Marino PA, Thorgeirsson SS. Regulation of 2-acetylaminofluorene-and 3-methylcholanthrene--mediated induction of multidrug resistance and cytochrome P450IA gene family expression in primary hepatocyte cultures and rat liver. Mol Carcinog. 1991;4(6):499-509. doi: 10.1002/mc.2940040614. PMID: 1686552.
Zubercová O, Babusíková O. The multidrug resistance in human leukemias. Minireview. Neoplasma. 1998;45(2):53-9. PMID: 9687882.
Gelhaus SL, Gilad O, Hwang WT, Penning TM, Blair IA. Multidrug resistance protein (MRP) 4 attenuates benzo[a]pyrene-mediated DNA-adduct formation in human bronchoalveolar H358 cells. Toxicol Lett. 2012 Feb 25;209(1):58-66. doi: 10.1016/j.toxlet.2011.11.021. Epub 2011 Nov 30. PMID: 22155354; PMCID: PMC3256298.
Boswell-Casteel RC, Fukuda Y, Schuetz JD. ABCB6, an ABC Transporter Impacting Drug Response and Disease. AAPS J. 2017 Nov 30;20(1):8. doi: 10.1208/s12248-017-0165-6. PMID: 29192381; PMCID: PMC5821141.
Zhang J, Zhang X, Li J, Song Z. Systematic analysis of the ABC transporter family in hepatocellular carcinoma reveals the importance of ABCB6 in regulating ferroptosis. Life Sci. 2020 Sep 15;257:118131. doi: 10.1016/j.lfs.2020.118131. Epub 2020 Jul 22. PMID: 32710948.
Vlaming ML, Lagas JS, Schinkel AH. Physiological and pharmacological roles of ABCG2 (BCRP): recent findings in Abcg2 knockout mice. Adv Drug Deliv Rev. 2009 Jan 31;61(1):14-25. doi: 10.1016/j.addr.2008.08.007. Epub 2008 Dec 7. PMID: 19118589.
Meyer zu Schwabedissen HE, Kroemer HK. In vitro and in vivo evidence for the importance of breast cancer resistance protein transporters (BCRP/MXR/ABCP/ABCG2). Handb Exp Pharmacol. 2011;(201):325-71. doi: 10.1007/978-3-642-14541-4_9. PMID: 21103975.
Liu L, Liu R, Liu Y, Li G, Chen Q, Liu X, Ma S. Cystine-glutamate antiporter xCT as a therapeutic target for cancer. Cell Biochem Funct. 2021 Mar;39(2):174-179. doi: 10.1002/cbf.3581. Epub 2020 Aug 4. PMID: 32749001.
Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021 Aug;12(8):599-620. doi: 10.1007/s13238-020-00789-5. Epub 2020 Oct 1. PMID: 33000412; PMCID: PMC8310547.
Schuetz EG, Schuetz JD, Thompson MT, Fisher RA, Madariage JR, Strom SC. Phenotypic variability in induction of P-glycoprotein mRNA by aromatic hydrocarbons in primary human hepatocytes. Mol Carcinog. 1995 Feb;12(2):61-5. doi: 10.1002/mc.2940120202. PMID: 7662117.
Lee A, Markovich D. Characterization of the human renal Na(+)-sulphate cotransporter gene ( NAS1) promoter. Pflugers Arch. 2004 Aug;448(5):490-9. doi: 10.1007/s00424-004-1251-z. Epub 2004 Jun 12. PMID: 15197597.
Burchiel SW, Thompson TA, Lauer FT, Oprea TI. Activation of dioxin response element (DRE)-associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-quinone in MCF-10A human mammary epithelial cells. Toxicol Appl Pharmacol. 2007 Jun 1;221(2):203-14. doi: 10.1016/j.taap.2007.02.020. Epub 2007 Mar 13. Erratum in: Toxicol Appl Pharmacol. 2008 Feb 1;226(3):345-6. PMID: 17466351; PMCID: PMC2020824.