An Endpoint of the Route from Xenobiochemistry (part 2) through Dioxin studies (part 3) to Xenovirology (part 4)

XENOTOX, Inc.

New York Corporation (Incorporated 08/29/2005) – New York S Corporation (since 2013) – Tax ID: 203535033

https://www.corporationwiki.com/p/2q39xk/xenotox-inc

XENOTOX, Inc. provides innovation and consulting services to the life sciences academia and industry.

It focuses on two science/biotech research areas both originated from previous discoveries, namely:

1) Concept of Xenobiotical Virology
2) Development of New, Clinically Useful Long-Acting Medicines by Site-Directed Modification of Drug Structure*

*The content of this subject is truncated due to patenting process requirements_

Preamble to the Concept of Xenobiotical Virology

(for more details please see Chapter 4 in this Website) The concept originated from surprising results obtained in late 80s, after Dr. Ilya Tsyrlov suggested to his former colleague Dr. Andre Pokrovsky of Research Virology Center “Vector” to test effects of dioxin (2,3,7,8-TCDD), the most potent xenobiotic so far known, on HIV-1 replication in CD4+ lymphoid cells. Alternatively to anticipated toxic effect of pleiotropic dioxin, we’ve registered a several-fold increase of RT activity and viral antigen, and a substantial trans-activation of HIV-1 LTR-CAT construct. However, due to stimulatory effects on HIV-1 of non-physiologic concentration of TCDD (250 ppt, whereas current background level in the general human population is ~4 ppt), the phenomenon (which was later confirmed in other labs) remained sui generis until 2002. That year, an up-regulation of human cytomegalovirus (hCMV) in human cells was shown using 10 ppq TCDD, a level much lower than current background level. That turned to vital reality a triggering effect on human viruses of body burden dioxins well known for their extremely long serum half-time (for e.g. TCDD 7–8 years) in humans. Also in 2002, a clear path to the underlying mechanisms of viral up-regulation by dioxin was highlighted in “Species DRE Summary”. Namely, _in cilico _computational method identified some “dioxin response elements” (DRE) in the 5’-flanking regions of several human viruses. To that very point, TCDD exerts its effects by activating endogenous cellular Ah receptor (AhR), a transcriptional factor known to induce (in a complex with TCDD and Arnt, a nuclear AhR translocator) expression of an entire battery of mammalian genes by virtue of DRE in their promoters. Eventually, we suggested some human viruses might be novel target genes for dioxin- activated AhR-Arnt complex in human host cell. All the above constitute four level approach to the problem of xenobiotic-virus relationships in human cells.

Computational Level

We used to use a computational search for DRE in viral genes performed by SITECON, a powerful tool for detecting conservative conformational and physico-chemical properties in transcription factor binding site alignments and for site recognition. Earlier SITECON efficiently detected all proved functional DREs in human CYP1A1 and CYP1B1, as well as DRE in human genes encoding AhR and proteins of its cytosolic and nuclear complexes. A total of 13 bona fide DRE, all including the substitution intolerant core sequence (5’-GCGTG-3’) and SITECON-selected adjacent variable sequences were used to detect the above properties for the viral DRE site, and conformational similarity score threshold of 0.95 was utilized to rank identified DRE. Eventually, for hCMV it was found that regulatory region of the genes encoding IE gp/UL37 has 5 potentially active DRE, 1.65 kb/UL36 – 6 DRE, pp65 – 7 DRE, pp71 – 7 DRE, and pp150 –10 DRE. Contrarily to that, each gene of different hepatitis B virus (HBV) proteins, as well as HIV-1 LTR, has a single promoter DRE. Aligned with the findings (or planned studies) shown in the next biological level, SITECON recognized that several known cancer-associated human viruses possess multiple DREs in their promoters. Thus two Epstein-Barr virus (EBV) promoters, L1A and L1, each contain 16 DRE, and gene of EBV R1 145K has 11 DRE. Also, genes encoding some major proteins of herpes simplex virus (HSV) type 1 have from 7 to 8 promoter DRE.

Biological Level

Going along with the above computational data, productions of infectious HIV-1 in MT4 cells, HCMV in THP-1 cells, and HBV in HepG2 cells were experimantally determined using plaque assay. Viral DNAs were determined by hybridization and PCR. The same approach is planned (and other virologists are also welcome to contribute) while studing TCCD effects on all of the above mentioned human viruses possessing promoter DRE, especially viruses linked to inflamation and malignacies. However, inasmuch as the concept was initiated with the data that sub-nanomolar dioxin able to activate DRE-containing viruses, such as HIV-1 and HBV, those viruses become beyond the scope of our recent interests, as active non-physiologic TCDD concentrations correspond well with a single promoter DRE in HIV-1 and HBV detected by SITECON. Contrary to that, up-regulation of hCMV in human cells by super-low 10 ppq dioxin was commensurate with SITECON data on 6 to 10 active DRE in promoter of different hCMV genes. So, if juxtapose DRE numbers with experimental results, our current interests concentrate on the most susceptible candidate human virus to be augmented with body burden dioxin, namely on viruses possessing at least similar to hCMV number of active promoter DRE, such as EBV and HSV. As virus-host interactions are crucial for the outcome of infections, our another approach is to reveal whether body burden TCDD regulates activity of DRE-possessing genes encoding components of antiviral pathways in infected cells? Thus we already indicated that human gene encoding NS1 binding protein of type A Influenza virus (AIV) have at least two active promoter DRE, and NS1 content icreased after treating of cells with TCDD at concentrations slightly above its body burden level. Overproduction of NS1 is known to prevent production of antiviral interferon. Also, in addition to computational findings of multiple active DRE in promoter region of two HSV-1 genes, human genes encoding major “proviral” chemokine RANTES/CCL5, and transcription factors NF-κB3/p65/ RelA and STAT3, all possess 7 to 9 active 5’ upstream DRE, which makes these genes more susceptible to TCDD-AhR-Arnt transcriptional complex. So, the above strongly suggest that body burden dioxin might promote HSV-1 infection.

Population (epidemiological) level

Since late 80s, a collaboration of Tsyrlov's lab with partner organization, the “Tropical Research Center” in Hanoi, revealed a prevalence of morbidity and mortality rates from viral infections in the mostly contaminated with dioxin-like compounds areas (provinces) of Vietnam, China and Taiwan. The interference of dioxins and NS1 in poultry and wild birds was found, as regions where birds died of H5N1 strain of AIV in China and Vietnam are regions where water and soil are heavily contaminated with dioxins. The experimental data with human NS1 shown in a previous paragraph, suppose that in East Asian countries human cohorts exposed to higher levels of dioxins, its body burden is a promotional factor for seasonal AIV outbreaks, and might strongly facilitate spreading of the H5N1 (or its modern modifications) if avian flu pandemic were to occur.

Preventive intervention (medico-biological) level

Mechanistic data obtained in the above research allow searching for inhibitors of human viremia and virally-driven inflammation and malignancies among antagonists ligands of cytosolic Ah receptor of infected host cells, or among modifiers of AhR-Arnt transcriptional complex binding to viral DRE.

Wikipedia article about Dr. Tsyrlov

MAJOR ACHIEVEMENTS IN CLINICALLY APPLIED AREAS:

• Cirrhosis: Modeling of Human Laennec’ Type of Cirrhosis.

• Cholestasis: Invention in vivo/in vitro dynamic comparison of destructive effects of cholic acids on microsomal phospholipids and CYP.

• Cancer: Newly Models of Chemical Carcinogenesis.

• Alcoholic Liver Disease: Revealing of CYP1A2 as Major Alcohol-Metabolizing Enzyme in Human Liver.

• Inflammation: Dioxin-Activated Herpes Viruses Linked to Inflammatory Pathways in Human Cells.

• Site-Directed Structural Modification of Clinically-Used Analgesics, Synthetic Opioids, and Antimalarials.

MAJOR ACHIEVEMENTS IN BASIC BIOMEDICAL SCIENCES:

• Revealing of "Substrate-Type" Induction Mechanism for CYP2B Enzymes by Phenobarbital-like Xenobiotics

• Usage of “Mutual Depletion Inhibition System” for Quantification of Membrane-Bound CYP Active Centers

• Comparative Enzyme-Kinetic Evaluation of cDNA-expressed, Purified and Microsomal Human CYPs

• Using Protonophores to Demonstrate Hydrophobic Zones in Microsome Membrane Specific for CYP Isozyme Active Centers

• Revealing a Koshland-Type Plasticity of CYP Active Center Determining its Inducer-Driven Substrate Specificity

• Discovery of trans-Activation Effects of 2,3,7,8-TCDD on HIV-1, CMV, HPV, EBV, HSV and HBV in Human Target Cells

In Cilico and Experimental Discovery of Potentially Active Promoter DREs in Human Dormant Viruses, and in Mammalian Genes Encoding Cellular Factors, Cytokines, and Cytosolic Ah Receptor Complex Components

• Inception and development of XENOBIOTICAL VIROLOGY as interdisciplinary biomedical field

Education and Scientific Occupation

Ilya Tsyrlov attended Novosibirsk Medical University, Russian Federation (1964-1970) graduating with M.D. degree (with distinction) in Internal Medicine, Diploma No. P467542 (1970).

IMG_0933

Graduate student in 1970

In 1973, he got a Ph.D. degree in Biochemistry, #### Theses: "Structural and Functional Changes of Biological Oxidation Systems During Liver Cirrhosis Development". Scientific Supervisor: Prof. V. Lyakhovich. Official Opponents: Prof. R. Salganik, Prof. Yu. Izumov.

In 1983, Tsyrlov earned a higher doctorate degree of D.Sc. degree (Doctor of Biological Sciences, Specialty: Biochemistry) from Institute of Experimental Medicine, Russian Academy of Sciences. #### Theses: "INDUCTION BY XENOBIOTICS, AND FUNCTIONAL PROPERTIES OF MEMBRANE-BOUND MONOOXYGENASES". Supervisor: Prof. V. Lyakhovich; Official Opponents: Academician R. Salganik, Prof. A. Archakov, Prof. V. Gaitzhoki.

For 20 years held progressively responsible positions of Research Team Leader (1972-79), and Head of Laboratory of Xenobiochemistry (1979-92), at Institute of Experimental and Clinical Medicine (since 1998 - Institute of Molecular Biology and Biophysics (http://www.imbb.soramn.ru/), Russian Academy of Sciences.

Chronologically, there are pictures of Dr. Tsyrlov' dear colleagues throughout his term as a scientist in the former Soviet Union:

founding four machos, the late 1960s
The late 1960s. "The Captain and Three Musketeers": V. Lyakhovich, A. Panov, V. Mishin, I. Tsyrlov.

1970s
The 1970s: V. Lyakhovich, V. Mishin, A. Panov, V. Ostashevsky, O. Khatsenko, V. Solovjev (late), K. Gerasimov, unknown person.

1980s
The 1980s: Yu. Levin, N. Gutkina, K. Gerasimov, N. Kozlovskaya, V. Ostashevsky, A. Grishanova.

1990s
The 1990s: N. Slinko, O. Chasovnikova, N. Subhankulova, I. Tsyrlov (visited from USA), S. Kovalenko, V. Vavilin, A. Grishanova, I. Kessova, N. Polyakova, A. Panov, unknown person, L. Gulyaeva.

2000s
The 2000s: I. Tsyrlov (visited from USA), L. Gulyaeva, V. Lyakhovich.

In 1990, the US National Institutes of Health (NIH) designated Tsyrlov as "internationally recognized scientist with a distinguished record of accomplishment", and hired him as a Senior Enzymologist at a renowned Laboratory of Molecular Carcinogenesis (headed by Harry Gelboin), National Cancer Institute/NIH, where Tsyrlov worked till 1995.
Tsyrlov's office in LMC, National Cancer Institute, NIH

Thereafter, he held positions of Research Associate Professor/Professor/Visiting Professor at the Department of Medicine and the Division of Occupational and Environmental Medicine, Mount Sinai School of Medicine (since 1996 - Icahn School of Medicine at Mount Sinai), New York, NY. In 2005, Tsyrlov founded the Xenotox, Inc., a life sciences consulting company certified with New York State, where he served a Chief Scientific Officer. In 2009, Tsyrlov became the company's President/CSO. The Xenotox, Inc. is implementing an earlier discovered site-directed synthesis of long-acting medications, and thoroughly studying the transactivation of the human herpesviruses by bodily dioxin in the picomolar range.

Recognitions and honors

Tsyrlov was endorsed by the governmental agency, the Higher Attestation Commission of the Ministry of Education and Science, awarding him title of a “Senior Research Scientist” (certificate #CH 18029, 1980), thereafter elevated to a distinguished level quoted for Doctors of Sciences (certificate BL 0011240, 1983).

DSci
RAS Academician Abel Aganbegyan handed over a Doctor of Sciences Diploma (autumn of 1983).

Tsyrlov had participated in the organizing drug metabolism scientists from 45 countries into International Society for Study of Xenobiotics, ISSX (www.issx.org), which currently is one of the largest research societies worldwide, and has served a Regional Editor of ISSX Newsletter (1981-90), a member of the International Scientific Affairs Committee (1992-99) and Nominating Committee (1991-97). In 2015, the ISSX Council elected Tsyrlov its Emeritus Member/Fellow

IMG_0922
With ISSX founder Academician Ron Estabrook and Prof. Fred Guengerich at Xenobiochemistry Congress in Bratislava (1980).


Editorship at the ISSX journal (back cover)

In 1989, Tsyrlov got a special invitation from Robert Wood Johnson Medical School, The Environmental and Occupational Health Sciences Institute, Rutgers Biomedical and Health Sciences to deliver the Rutgers Distinguished "First Special Lecture of the International Program" entitled "Biological & Medical Aspects of Polychlorinated Dioxins".

In 1992, Tsyrlov was granted the Alien of extraordinary ability EB-1 visa green card category, reserved for distinguished foreign national professionals.

In 1992, Tsyrlov was selected by the World Health Organization WHO Council to final candidate for the post of Director of the International Agency for Research on Cancer (IARC).

WHO/IARC

In 2006, Tsyrlov was invited by US EPA's Distinguished Lecture Series to deliver a seminar on "The Role of Body Burden 2,3,7,8-TCDD in Triggering Malignancy-Associated Human Viruses: From Early Data to Mechanistic Concept" (www.researchgate.net/publication/342987077).

In the 1980s-2000s, he has been invited to deliver special lectures and seminars at universities of 14 countries, research companies (Hoechst AG, Frankfurt, Merck Sharp/Rahway, Boehringer Ingelheim/Ridgefield, etc.) and governmental agencies (NIH, EPA, DHHS, CDC, Cancer Research UK). Tsyrlov has served a member of Organizing Committee of International meeting DIOXIN'1985, Germany; International ISSX Meeting'1995, USA; DIOXIN meeting'2006, Norway; Alzheimer's Association International Conference'2016, Canada; Influenza Congress'2017, UK; Infectious Diseases Congress'2018, Japan; etc. He is an Editor of “Cytochrome P450 and Environment” book (1987), and several congressional proceedings on drug metabolism and various aspects of hazard xenobiotics. He served a Session Chair/Plenary lecturer at eleven national/international meetings, and a Keynote Speaker at nine national/international congresses. Since the 1990s, Tsyrlov has been a senior reviewer of the International Human Frontier Science Program. Also, he served an officer/fellow of European Society of Biochemical Pharmacology, Liver Diseases and Hepatitis Program, ASBMB, American Cancer Society, Society of Environmental Toxicology and Chemistry, The Biochemical Society, AAAS, SOT, FAS, and Alzheimer Research Forum.

An open-minded public speaker, Tsyrlov has exposed environmental issues of hazard xenobiotics that affect human health. He addressed environmental health problems that existed throughout the Soviet Union/Russia (“The Ailing Mother Russia”. ''Environmental Health Perspectives'' 102, #2, Feb 1994). The same year Tsyrlov was invited as a distinguished member to US CDC and Citizen Ambassador Program' delegation to attend a conference with the Russian Ministry of Environmental Protection, held in Moscow. With the President of Fishkill Ridge Caretakers, Inc., Peter Rostenberg, MD, Tsyrlov petitioned on behalf of the Superfund Research Program to then Governor of New York State George Pataki to support clean up of the toxic polychlorinated biphenyls deposited over 30 years by the General Electric Corporation in the Hudson River (“GE wants to stick to own PCB control” and other articles in the ''Poughkeepsie Journal'' (2000-02).

In 2006, Tsyrlov was specially invited to co-chair the International Scientific Conference “Victims of Agent Orange/Dioxin in Vietnam – the Expectation” in Vietnam, where he made two keynote scientific communications on damaging effects of dioxin-like compounds (DLC). Tsyrlov chaired meetings of American and Vietnamese widows commemorating Vietnam War fallen warriors, for that the Vietnamese government bestowed him with Ly-Viet Hands antique. In 2005-07, Tsyrlov consulted the US government in international issues on dioxins toxicity and was awarded by US Vice President Richard Cheney.

Tsyrlov has published 5 monographs

12 reviews and book chapters, and 260+ peer-reviewed papers in world's academic research journals with the SNIP of 4.0 and higher, such as Archives of Biochemistry and Biophysics; Biochemistry; The Biochemical Journal; Carcinogenesis; Chemosphere; Drug Metabolism and Disposition; Chemico-Biological Interactions; FEBS Letters; Experimental and Molecular Pathology; Hoppe-Seyler's Zeitschrift für Physiologische Chemie; Journal of Viral hepatitis; Lancet Infectious Diseases; Alcoholism: Clinical and Experimental Research; Life Sciences; International Journal of Infectious Diseases; Environmental Health Perspectives; Alzheimer’s and Dementia (The Journal of the Alzheimer’s Association); Virology Research Journal; European Respiratory Journal; Drug Metabolism Reviews. By author-level scientometrics analysis, Tsyrlov's i6-index is 28, and his published results have been full-text read/downloaded by 56,000 scientists worldwide (https://www.researchgate.net/profile/Ilya_Tsyrlov).

PUBLICATIONS

Books

Ilya Tsyrlov: "POLYCHLORINATED DIOXINS: BIOLOGICAL AND MEDICAL ASPECTS". The Library of National Academy of Sciences, 1990, 239 pp. + illustrations edited by Academician Valentin Vlassov, 01/1990; NAUKA Publishing House (Publisher for National Academy of Sciences),., ISBN: BBK P 284.6 50300-887-1990

Vyacheslav Lyakhovich and Ilya Tsyrlov (editors) "Cytochrome P-450 and Environment". 1987, 411 pp. Academy of Sciences Pubnlishing House.

Vyacheslav Lyakhovich and Ilya Tsyrlov. "INDUCTION OF XENOBIOTICS METABOLIZING ENZYMES". Russian National Academy of Science, Edited by Academician A.A. Yasaitis, 1981; Nauka-Science Press, 341 pp.., ISBN: 50300-737 18-14-1980

Vyacheslav Lyakhovich and Ilya B. Tsyrlov: "STRUCTURAL ASPECTS OF MONOOXYGENASES BIOCHEMISTRY", Edited by Prof. R.I. Salganik, 1978; 337 pp., "Nauka-Science Press", ISBN: 21003-743 686-78

Book Chapters

Ilya Tsyrlov, V. Ostashevsky, K. Gerasimov, V. Rumak: Characteristics of Hepatic and Lymphocyte Monooxygenases in South Vietnam' People with Chlorophenoxy Herbicides Exposure. IARC monographs on the evaluation of carcinogenic risks to humans. Volume 113., Supplement 06/2015; volume 113 06/2015; World Health Organization, International Agency for Research on Cancer, WHO.

Ilya Tsyrlov, Vladimir Ostashevsky: 389:;<= <8>?@9@<=ABC@D@ @>89A;C8E >9;C@F8@:8>@G G A8<H@I8:=J >?@G8 K8:;A;L .B;:C=<=, M@NG;?D=GO8J9E G@PN;L9:G8Q N8@>98C@G. «012345 – 36789123*0:4;5 21-<& "82:», Russian National Acfdemy of Science, Institute of Evolution after Severtsev edited by G. Sofronov, V. Rumak, 09/2006: chapter 3(=>?@A @(B.&=&@A/CD&<& &B(=/?D($ B=?D&E(&>(B&' ' /(@F&G(>A% B.&'( H(>?/?I "C?>DA@A, J&K'?.<A'L(%=$ '&MK?I=>'(N K(&B=(D&': pages 77-95; Maik NAUKA/Elsevier Interperiodica.

Ilya Tsyrlov: DIOXIN-LIKE CHLORPHENOXY HERBICIDES MIGHT AUGMENT HUMAN COMMON VIRUSES ASSOCIATED WITH CELL MALIGNIZATION1. "Victims of the Agent Orange/Dioxin in Vietnam", March 2006 edited by Ngueng Thi Bing, President VAVAOD, Le Thi Nham Tuyet Director of Research Center, 03/2006: pages 149-155; FFRP Publishing House, Hanoi, Vietnam.

Ilya Tsyrlov: Factors Controlling Induction of Different Forms of P-450 in the Liver. MOLECULAR MECHANISMS OF CELLULAR HOMEOSTASIS, National Academy of Science, Siberian Division edited by RAS Corresponding Member I. Gitelzon, 01/1987: Chapter "Factors Controlling Induction of Different Forms of P-450 in the Liver", pp. 130-154; NAUKA Publishing House., ISBN: 50303-747 18-14-1987

Ilya Tsyrlov: The Membrane Aspects of the Regulation of Monooxygenases. Industrial and Environmental Xenobiotics, Edited by J. Fouts, I. Gut, 01/1978: pages 87-99; Springer, Amsterdam.

Ilya Tsyrlov, Vyacheslav Lyakhovich: Genetic Variations in Cytochrome P-450(P-448) Catalytic Centers Activities in Relation to Subsequent Conjugation Reactions. CONJUGATION REACTIONS IN DRUG BIOTRANSFORMATION, Amsterdam-New York-Oxford edited by A. Aitio, 01/1978: chapter GENETIC VARIABILITY IN DRUG METABOLISM: pages 136-154; Elsevier/North-Holland Biomedical Press., ISBN: 0-444-80090-5

Ilya Tsyrlov, N. Rivkind, V. Lyakhovich: Metabolism of Polycyclic Hydrocarbons in the Liver of Different Murine Strains in the Course of Chemical Carcinogenesis. Industrial and Environmental Xenobiotics, Edited by Editors: J. Fouts, I. Gut, 01/1978: pages volume 2, pp. 164-184; Springer, Amsterdam.

V. Lyakhovich, Ilya Tsyrlov, V. Mishin, O. Gromova: Reconstitution of the Microsomal System of Xenobiotic Metabolism. Industrial and Environmental Xenobiotics, Publisher:, Edited by Editors: J. Fouts, I. Gut, 01/1978: pages 1: 99-108; Springer, Amsterdam.

Ilya Tsyrlov, O. Gromova, V. Lyakhovich: Different Phospholipid-Dependent Hydrophobic Zones in Microsomal Membrane Surrounding Cytochrome P-450. Physico-Chemical Basics of Function of Supermolecular Cellular Structures (dedicated to the late Academician A. Belozersky), Edited by A. Belozersky, V. Skulachev, 01/1974: pages volume 2, pp. 120-133; Moscow University Academic Press, Moscow.

O. Gromova, Ilya Tsyrlov, V. Mishin, N. Zakharova, V. Lyakhovich: Cytochromes P-450 and P-448 Have Different Resistance to the Factors Destabilizing Microsomal Membrane. Physico-Chemical Basics of Function of Supermolecular Cellular Structures (dedicated to the late Academician A. Belozersky),, Edited by Edited by A. Belozersky, V. Skulachev, pages volume, 01/1974: pages vol. 1:61-67; Moscow University Academic Press× Moscow.

Journal publications

PDF list of journal publications.

Patent

Ilya Tsyrlov, K. Gerasimov: Mode of Production of Long-Acting Drugs Capable of Induction of Mono-Oxygenase System in Human Liver. Ref. No: 145759 3 (Claim # 4105655), Year: 05/1988

Document4.pdf

Conference Proceedings

PDF list of conference proceedings.

List of major coauthors. List of collaborators and fellow scientists from LinkedIn.