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Biotransformation and Toxicities of Aristolochic Acids

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Mechanisms of Genome Protection and Repair

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1241))

Abstract

Environmental and iatrogenic exposures contribute significantly to human diseases, including cancer. The list of known human carcinogens has recently been extended by the addition of aristolochic acids (AAs). AAs occur primarily in Aristolochia herbs, which are used extensively in folk medicines, including Traditional Chinese Medicine. Ingestion of AAs results in chronic renal disease and cancer. Despite importation bans imposed by certain countries, herbal remedies containing AAs are readily available for purchase through the internet. With recent advancements in mass spectrometry, next generation sequencing, and the development of integrated organs-on-chips, our knowledge of cancers associated with AA exposure, and of the mechanisms involved in AA toxicities, has significantly improved. DNA adduction plays a central role in AA-induced cancers; however, significant gaps remain in our knowledge as to how cellular enzymes promote activation of AAs and how the reactive species selectively bind to DNA and kidney proteins. In this review, I describe pathways for AAs biotransformation, adduction, and mutagenesis, emphasizing novel methods and ideas contributing to our present understanding of AA toxicities in humans.

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Abbreviations

AA-I:

aristolochic acid I or 8-methoxy-6-nitrophenanthro-[3,4-d]-1,3-dioxole-5-carboxylic acid

AA-II:

aristolochic acid II or 6-nitrophenanthro-[3,4-d]-1,3-dioxole-5-carboxylic acid

AAN:

aristolochic acid nephropathy

AAs:

collective term for various aristolochic acids

AL-DNA:

aristolactam-DNA adduct

AL-I:

aristolactam I

AL-II:

aristolactam II

AL-II-NOH:

N-hydroxyaristolactam II

AL-I-NOH:

N-hydroxyaristolactam I

AL-I-N-OSO3H:

aristolactam-I-N-sulfate or N-sulfonyloxyaristolactam I

BEN:

Balkan endemic nephropathy

ccRCC:

clear cell renal cell carcinoma

CYP1A2/1:

cytochrome P450 1A1 and cytochrome P450 1A2

dA-AL-I:

7-(deoxyadenosine-N6-yl)-aristolactam I

dA-AL-II:

7-(deoxyadenosine-N6-yl)-aristolactam II

dG-AL-I:

7-(deoxyguanosin-N2-yl)-aristolactam I

dG-AL-II:

7-(deoxyguanosin-N2-yl)-aristolactam II

FFPE:

formalin-fixed paraffin-embedded

HCC:

hepatocellular carcinoma

HPLC:

high performance liquid chromatography

IHCC:

intrahepatic cholangiocar-cinoma

MPS:

microfluidic physiological system also known as organs on chips

NAT:

N-acetyltransferase

NQO1:

NAD(P)H:quinone oxidoreductase 1

NR:

nitroreduction

OATs:

organic anion transporters

PAGE:

polyacrylamide gel electrophoresis

PAPS:

3′-phosphoadenosine-5′-phosphosulfate

PHS-1 and PHS-2:

prostaglandin H synthase 1 and 2, also known as cyclooxygenases 1 and 2, Cox-1 and Cox-2, respectively

POR:

also known as CYPOR, cytochrome P450 oxidoreductase

SAR:

structure activity relationship

spp:

species

SULT:

sulfotransferase

TCM:

Traditional Chinese Medicine

TLC:

thin layer chromatography

UPLC-ESI/MSn:

ultraperformance liquid chromatography-electrospray ionization/multistage mass spectrometry

UTUC:

upper urinary tract urothelial carcinoma

XDH or XO:

xanthine dehydrogenase/xanthine oxidase.

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Acknowledgements

The author would like to express her deep gratitude to the Laufer Family and Zickler Foundations for financial support. This review was made possible by the many contributions from my colleagues and collaborators. Thomas Rosenquist developed monoclonal antibodies, which facilitated our studies of aristolochic acid metabolites and aristolactam-proteins in animals. Kathleen Dickman led translational studies of aristolochic acid nephropathy and urothelial cancer. Francis Johnson and Radha Bonala developed novel syntheses of aristolochic acids. Masaaki Moriya and Keiji Hashimoto conducted studies of mutagenesis of aristolactam-DNA adducts and collaborated in our investigations of biotransformation pathways of aristolochic acids. Robert Turesky (University of Minnesota) established mass spectrometry-based methods for detection of adducted DNA. Robert Rieger and John Haley developed methods for quantification of aristolochic acids in complex samples. The author thanks Christopher E. Eyermann for editing the manuscript, and Kathleen G. Dickman, Thomas A. Rosenquist and Arthur P. Grollman for their edits, comments and suggestions, and Cinthia Alvarez-Buonaiuto for help in preparing the figures.

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  1. Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA

    Viktoriya S. Sidorenko

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  1. Viktoriya S. Sidorenko
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  1. Novosibirsk State University, Novosibirsk, Russia

    Dmitry O. Zharkov

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Sidorenko, V.S. (2020). Biotransformation and Toxicities of Aristolochic Acids. In: Zharkov, D. (eds) Mechanisms of Genome Protection and Repair. Advances in Experimental Medicine and Biology, vol 1241. Springer, Cham. https://doi.org/10.1007/978-3-030-41283-8_9

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