Carahealth Heavy Metal/Plastic Detoxification Plan
Your health plan includes an initial Skype consultation & 2 follow up consultations.
Carina Harkin holds 3 level 8 Bachelor of Health Science degrees in Complementary and Alternative Medicine (CAM), being the world’s first triple degree CAM graduate, with a degree in Acupuncture, Naturopathy (Nutrition and Herbal Medicine) and Homeopathy. Carina worked as an acupuncturist and sports nutritionist for an Australian Football League team. Receiving substantial training in pharmacology & having worked in pharmacies, Carina is adept in drug/nutrient and drug/herb safety and specialises in matching the pharmacological action of drugs with active constituents found in herbs. Carina has an online herbal dispensary and supplies organic pharmacy grade herbal extracts worldwide. Carina has experience treating antimicrobial resistant disease, currently beyond the biomedical approach, including MRSA, MDR-TB, MDR Streptococcus pneumonia & Haemophilus influenza, MDR Candida, Neglected Tropical Disease (NTD) including Dengue, Ross River/ Barmah Forest virus etc, and the rising tide of Non Communicable Disease including autoimmune, allergic and inflammatory disease. Carina holds a teaching qualification and is an experienced lecturer with 20 years clinical experience. Carina has worked in Public Health, as an acupuncturist at the Northern Hospital Melbourne, where she conducted A Prospective, Randomised Control Trial of Acupuncture for Select Common Conditions within the Emergency Department and in Box Hill Hospital’s Drug & Alcohol Rehabilitation Unit. Carina’s goal is to see the integration of CAM into mainstream healthcare hence she is completing a Masters in Public Health. The WHO are looking at the role Traditional Medicines have in keeping populations healthy & Carina wants help shape future Public Health Policy to improve Global Health Outcomes using Traditional Medicines. Carina is writing her dissertation on The Use of Herbal Medicine to Address the Greatest Global Threat; Antimicrobial Resistance.
Carina Harkin & Dr Roby Parker, A Prospective, Randomised Control Trial of Acupuncture for Select Common Conditions within the Emergency Department, Journal of Chinese Medicine, Number 85, pp 45-52., October 2007
Carina Harkin, Effect of Homeopathic Calcium on Bone Density, Homoeopathic Links, Vol. 21: 1–6 6. Spring 2008.
Carina Harkin BHSc.Acu.BHSc.Nat.BHSc.Hom. Cert IV TAE.
Why excess toxins damage health
If not adequately supported or in the case of excessive POPs, Phase I is induced (sped up) producing high levels of damaging free radicals. If these reactive molecules are not metabolised by Phase II conjugation damage to proteins, RNA, & DNA occurs causing genetic mutation. Disruption of Phase I can damage proteins, RNA, and DNA within the cell and is seen as an important factor in the pathogenesis of cancer. The treatment principle in plastic detoxification is to inhibit Phase I P450 (modification) and to induce Phase II detoxification (conjugation).
Heavy metals such as cadmium, lead and mercury are common air pollutants resulting from various industrial activities.Heavy metal pollution is one of the major concerns of the century with sources being both anthropogenic (human-made) and naturogenic (from nature) with the health effects well documented. (8) The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury and arsenic. These metals have been extensively studied and their effects on human health regularly reviewed by international bodies such as the WHO. (9) Almost all heavy metals are serious toxicants as carcinogens. (10) There are different sources for heavy metals in the environment. These sources can be both of natural or anthropogenic origin (chiefly of environmental pollution and pollutants).
8 million tons of plastic enters the oceans each year. Microplastics are ubiquitous in marine waters, from deep ocean sediments to polar icecaps. (11) Billions of people are drinking water contaminated by plastic particles with 83% of samples found to be polluted. The average number of fibres found in each 500ml of tap water sample ranging from 4.8 in the US to 1.9 in Europe. (12, 13) In Germany plastic fibres & fragments were found in all 24 beer brands tested, as well as honey & sugar. This study concluded average person ingests 5,800 particles of plastic per year from beer, salt & tap water, with largest contribution coming from tap water (88%). (12) An Irish study (June 2017) found microplastic contamination in a handful of tap water & well samples. (14)
The Orb study tested 259 bottled water brands from 19 locations in 9 countries across 11 different brands were found to contain on average 325 plastic pieces for every litre of water. (15)Plastic fibres in bottled water brands are twice as high as those found in tap water.PETE (recycling code 1) does not contain bisphenol A (BPA)/Phthalates but studies find antimony (toxic phthalate 'plasticiser' used to make plastics flexible), leaches from PET bottles placed in heat for prolonged periods. (16)
9 different plastics found in all human stools tested posing a threat to Public Health. (17-19)
Most plastic products release oestrogenic otherwise known as Endocrine Disrupting Chemicals (EDCs) which have a variety of negative health effects. (20) EDCS include organochlorine pesticides, poly-chlorinated biphenyls, BPA, phthalates, dioxins & furans. (21)
EDC diseases & disorders include female & male infertility, (22) low sperm count, genital malformations, intersex variation IV, sharp increase in gender dysphoria, transgender & gender neutral (LGBTQI existed pre-industrial revolution), precocious puberty in young girls (risk factor for breast cancer), adverse pregnancy outcomes such as premature birth/low birth weight.
Neurobehavioral disorders include cognitive, motor & sensory deficits, neurological impairments (NIs) including neuropathies, neurodevelopmental disorders) autism & attention deficit hyperactivity disorder (ADHD), neurodegenerative diseases including Alzheimer's disease, Parkinson's disease & amyotrophic lateral sclerosis (ALS). Exposure associated with persistent organic pollutants (POPs), plastic exudates BPA & phthalate. (23)
Other health effects include hormone dependent tumours including breast, endometrial, ovarian, prostate, testicular and thyroid, metabolic disorders including Polycystic Ovary Syndrome (PCOS), Metabolic syndrome (evidence shows EDCs may contribute to the obesity pandemic evolution & metabolic disorders including Type 2 Diabetes (T2D) (24) and atopic disorders such as. allergies, asthma & atopic dermatitis. (25)
Detoxification is not Quackery it is called Biotransformation
Research into human biotransformation and elimination systems continues to evolve. In medical terms promotion of toxicity is called bioaccumulation and detoxification is called Biotransformation.Bioaccumulation is a term used to describe the accumulation of persistent organic pollutants (POPs) (1) also known as persistent toxic substances (PTSs) (2) which are detected at high levels in blood and urine samples taken for the National Health & Nutrition Examination Survey (NHANES) conducted annually in US by CDC. POPs include Serum dioxins, furans & PCB and urinary phthalates and BPA. (26)
Heavy Metal Biotransformation
Heavy metal bioaccumulation inhibits Phase I cytochrome P450 (CYP) enzyme system. (27, 28) Disruption of CYP can damage proteins, RNA, and DNA within the cell and is seen as an important factor in the pathogenesis of cancer. Arsenic for example is methylated. (29) The treatment principle in heavy metal bioaccumulation is use herbal extracts shown modulate P 450 in combination with plant metallothioneins (MTs) and phytochelatins (PCs) to chelate heavy metals. Certain herbs have the ability to both induce and inhibit Phase I cytochrome P450 (CYP) enzyme systems.
BPA & phthalates are ingested plastic toxins.
Accumulation of BPA induces cytochrome P450 enzyme activities. (30)
In humans, ingested BPA is not extensively metabolised by cytochrome P 450 specifically CYP2C. (31)
BPA is also metabolite of glutathione conjugation. (32)
BPA is rapidly metabolised with glucuronidation conjugation. (33, 34) Minor amounts of BPA are conjugated with sulphate and also, glutathione. (32)
Transferases including sulfotransferases, glutathione-S-transferases (GSTs) are also involved in BPA conjugation. (35)
A fraction of absorbed BPA may distribute to body storage site(s) such as adipose tissue, followed by a slow, low-level release of BPA into the bloodstream. (36)
Phthalates undergo a series of phase I hydrolysis and phase II conjugation reactions and are subsequently excreted in faeces and urine (37)
Phthalates induce (cause overactivity) of cytochrome P450 (38) specifically CYP4 Enzymes. (7)
Phthalates are a metabolite of glucuronidation, (39, 40) glycine & sulphation conjugation. (40, 41)
Dioxins, furans & dioxin-like polychlorinated biphenyls (PCBs) are abbreviated names for a family of chemicals with similar toxicity & shared chemical characteristics. Dioxins & furans are inhaled & produced when plastic is burned. Dioxins & furans are also known as Tetrachlorodibenzo-p-dioxin (TCDD), the contaminant in Agent Orange (herbicide used in the Vietnam war).
Naturopathic Approaches to a Heavy Metal & Plastic Detoxification
Avoid drinking out of plastic bottles. Purchase the Carahealth Eco Water Filter
Place client on a limited therapeutic fast then a detoxification diet
Fasting is Calorie Restriction (CR)
The benefits of CR are scientific fact. A therapeutic fast simulates the Calorie Restrictive Diet that scientists have touted for the main reason behind Okinawan longevity.Like CR, fasting also activates telomerase the anti-ageing enzyme. Fasting, like CR, improves how cells respond to stress, how they break down (autophagy), induces apoptosis (programmed cell death ie in cancer cells),(51)and alters hormonal balance. Autophagy in particular, is quality control inside cells. It is essential to maintain cellular homeostasis and to improve how the cell responds to stress. Autophagic activity declines with age, therefore fasting is anti-ageing. CR is neuroprotective (protects brain cells). (52) In relation to heavy metal accumulation, CR/fasting enhances Phase II Detoxification specifically increasing glucuronidation and Glycine conjugation, thus will assist in the elimination of heavy metals. (3)
Research shows dietary phytochemicals (chemicals in food) act as direct antioxidants to scavenge reactive oxygen species (free radicals). Dietary phytochemicals also regulate transcription factor Nrf2 [nuclear factor erythroid 2 (NF-E2). Nrf2 regulates the body's detoxification and antioxidant systems associated with phase II detoxification and antioxidant enzymes. (7) Metallothionein is a cysteine-rich protein that binds toxic metals such as mercury, cadmium, lead and arsenic.(4)Certain dietary patterns and nutrients increase metallothionein production. (7)
Apply Pharmacognosy to support Phase 1 & II detoxification pathways & apply chelation therapy using plant Metallothionein & phytochelatins
Why use Carahealth herbs?
Carahealth tonics are 1:1 strength organic or wildcrafted extracts, meaning 1 part herb to one part alcohol. There is no point using non organic herbs to assist detoxification.All scientific studies in pharmacognosy use herbal medicine extracts, not weaker tinctures.
The plan alternates 2 herbal detoxification tonics Carahealth Heavy Metal Detox and Carahealth Liver /Plastic Detox.
Objectives in Heavy Metal Detoxification
Carahealth Heavy Metal Detox (Carina’s 11 significant tonic decoction)
The first 10 herbs are the traditional Chinese herbal formula Shi Quan Da Bu Tang (10 significant tonic decoction), the 11th herb is alfalfa.
Sheng Di huang Rehmannia glutinosa
Bai Shao Paeonia lactiflora
Chuan Xiong Liqusticum wallichii
Dang Gui Angelica sinensis
Gan Cao Glycyrrhiza uralensis
Gin Seng Panax ginseng
Huang Qi Astragalus membranaceus
Gui Zhi Cinnamomum cassia
Fu Ling Poria cocos
Bai Zhu Atractylodes macrocephala
Alfalfa Medicago sativa
Shi Quan Da Bu Tang is traditionally used to tonify the Blood and Qi to treat anaemia, anorexia, extreme exhaustion, fatigue, kidney and spleen insufficiency and general weakness, particularly after illness and after chemotherapy. It has been found to potentiate (make it work better) chemotherapy and radiotherapy and inhibit malignant recurrences, prolong survival and prevent and ameliorate adverse toxicities in cancer treatment. (53) In Japanese herbal medicine (Kampo) the formula is known Juzen Taiho To and has been shown to increase expression of metallothioneins (MTs). (54) Shi Quan Da Bu Tang also increases transcription factor Nrf2 to support phase II detoxification thus regulate the body's detoxification and antioxidant system. (55) Alfalfa Medicago sativa contains heavy metal chelating plant metallothioneins. (5)
Objectives in Plastic Detoxification
Carahealth Liver /Plastic Detox Tonic
Andrographis Andrographis paniculata
Milk thistle Silybum marianum
Bupleurum Bupleurum falcatum
Globe artichoke Cynara scolymus
Barberry Berberis vulgaris
Turmeric Curcuma longa
Inhibit Phase I P450
Andrographis contains diterpenolactones which inhibits Phase I P450. (56)
Milk thistle Silybum marianum
Milk thistle significantly inhibits Phase I P 450. (57) The flavonolignans including silymarin(58)restore depleted glutathione (GSH) to assist glutathione conjugation. (59)
Bupleurum Bupleurum falcatum Chai Hu
Bupleurum contains saikosaponins which inhibit Phase I P450 enzymes (CYP1A2, CYP2C9 & CYP3A4) and flavonoids & steroids including, among others, rutin and quercetin which also inhibit Phase I P450 (CYP3A4). (56, 60)
Inhibit Phase I P450 & induce Phase II
Globe artichoke Cynara scolymus Yang Ji
Globe artichoke contains the flavonoid luteolin which inhibits Phase I P 450 (CYP 3A4 & CYP3A5)(61) and also the hydroxycinnamic acid, cynarin which stimulates glucuronidation conjugation. Artichoke has potent antioxidant activity & reduces toxin-induced reduction of glutathione reserves. (62)
Barberry Berberis vulgaris Fu Niu
Barberry contains the benzylisoquinoline alkaloid berberine which inhibits Phase I P 450. (63) Berberine, specifically increases endogenous antioxidants, glutathione peroxidase (GPx) & superoxide dismutase (SOD), both copper-zinc SOD (CuZn-SOD) & manganese SOD (Mn-SOD) to assist glutathione conjugation. (64)
Turmeric Curcuma longa Jiang Huang
Turmeric contains the diarylheptanoid curcumin which inhibits Phase I P 450 while inducing Phase II. (65, 66) Curcumin restores depleted GSH to assist glutathione conjugation. (67)
Curcumin also induces Nrf2 to increase antioxidant expression thereby protect against oxidative damage triggered by injury & inflammation. (68) Phase-II enzymes are regulated by Nrf2 which is involved in detoxification of AFB1.Aflatoxins B1 are genotoxic & carcinogenic compounds. Phase I P 450 enzymes are responsible for AFB1 bioactivation. Curcumin prevents AFB1-induced liver injury by modulating Phase I & Phase II enzymes. (69)
Carina Harkin BHSc.Nat.BHSc.Hom.BHSc.Acu. Cert.IV TAE. MPH (pending)
Carina Harkin holds 3 level 8 Bachelor of Health Science degrees in Complementary and Alternative Medicine (CAM), being the world’s first triple degree CAM graduate. Receiving substantial training in pharmacology & having worked in pharmacies, Carina is adept in drug/nutrient and drug/herb safety and specialises in pharmacognosy, matching the pharmacological action of drugs with active constituents found in herbs. Carina has an online herbal dispensary and supplies organic pharmacy grade herbal extracts worldwide. Carina has experience treating antimicrobial resistant disease, currently beyond the biomedical approach, including MRSA, MDR-TB, MDR Streptococcus pneumonia & Haemophilus influenza, MDR Candida, Neglected Tropical Disease (NTD) including Dengue, Ross River/ Barmah Forest virus etc, and the rising tide of Non Communicable Disease including autoimmune, allergic and inflammatory disease. Carina holds a teaching qualification and is an experienced lecturer with 20 years clinical experience. Carina has worked in Public Health, as an acupuncturist at the Northern Hospital Melbourne, where she conducted a world first trial A Prospective, Randomised Control Trial of Acupuncture for Select Common Conditions within the Emergency Department and in Box Hill Hospital’s Drug & Alcohol Rehabilitation Unit. Carina’s goal is to see the integration of CAM into mainstream healthcare hence she is completing a Masters in Public Health. The WHO are looking at the role Traditional Medicines have in keeping populations healthy & Carina wants help shape future Public Health Policy to improve Global Health Outcomes using Traditional Medicines. Carina has been treating bioaccumulation and helping people successfully eliminate heavy metal toxins for 20 years and presents her research at international conferences.
1.Pumarega J, Gasull M, Lee D-H, López T, Porta M. Number of Persistent Organic Pollutants Detected at High Concentrations in Blood Samples of the United States Population. PLOS ONE. 2016;11(8):e0160432.
2.Wong MH, Armour MA, Naidu R, Man M. Persistent toxic substances: sources, fates and effects. Reviews on environmental health. 2012;27(4):207-13.
3.Wen H, Yang H-J, An YJ, Kim JM, Lee DH, Jin X, et al. Enhanced phase II detoxification contributes to beneficial effects of dietary restriction as revealed by multi-platform metabolomics studies. Molecular & cellular proteomics : MCP. 2013;12(3):575-86.
5.Robinson NJ, Tommey AM, Kuske C, Jackson PJ. Plant metallothioneins. The Biochemical journal. 1993;295 ( Pt 1)(Pt 1):1-10.
6.Rea PA, Vatamaniuk OK, Rigden DJ. Weeds, Worms, and More. Papain's Long-Lost Cousin, Phytochelatin Synthase. 2004;136(1):2463-74.
7.Hodges RE, Minich DM. Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. Journal of nutrition and metabolism. 2015;2015:760689-.
8.WHO. Health risks of heavy metals from long-range transboundary air pollution. Germany 2007.
9.Jarup L. Hazards of heavy metal contamination. Br Med Bull. 2003;68:167-82.
10.Kim H, Jin Kim Y, Rok Seo Y. An Overview of Carcinogenic Heavy Metal: Molecular Toxicity Mechanism and Prevention2015. 232-40 p.
11.Jambeck JR, Geyer R, Wilcox C, Siegler TR, Perryman M, Andrady A, et al. Marine pollution. Plastic waste inputs from land into the ocean. Science (New York, NY). 2015;347(6223):768-71.
12.Mary Kosuth SMaEW. Anthropogenic contamination of tap water, beer, and sea salt. Plos One. 2018 April 11.
13.Mary Kosuth EVW, Sherri A. Mason, Christopher Tyree, Dan Morrison. Synthetic polymer contamination in Global drinking Water [Interent]. ORB 2017 May 16 [Available from: https://orbmedia.org/stories/invisibles_final_report/multimedia.
14.Anne Marie Mahon RO, Róisín Nash and Ian O’Connor. Research 210:Scope, Fate, Risks and Impacts of Microplastic Pollution in Irish Freshwater Systems. EPA GMIT; 2014.
15.Mason SA, Welch VG, Neratko J. Synthetic Polymer Contamination in Bottled Water. Frontiers in chemistry. 2018;6:407-.
16.Westerhoff P, Prapaipong P, Shock E, Hillaireau A. Antimony leaching from polyethylene terephthalate (PET) plastic used for bottled drinking water. Water research. 2008;42(3):551-6.
17.Editor KOSES. Nine different plastics found in human stools, research shows. The Irish Times. 2018 Oct 23.
18.Thompson A. Microplastics Have Been Found in People's Poop—What Does It Mean? Scientific American. 2018 Oct 24.
19.Wright SL, Kelly FJ. Threat to human health from environmental plastics. 2017;358.
20.Åke Bergman JJH, Susan Jobling, Karen A. Kidd and R. Thomas Zoeller. State of the Science of Endocrine Disrupting Chemicals Geneva: WHO UNEP Inter-organisation programme fro the sound managemnt of chemicals: A cooperative agreement among FAO, ILO, UNDP, UNEP, UNIDO, UNITAR, WHO, World Bank and OECD; 2012.
21.Hood E. Are EDCs blurring issues of gender? Environmental health perspectives. 2005;113(10):A670-A7.
22.Huo X, Chen D, He Y, Zhu W, Zhou W, Zhang J. Bisphenol-A and Female Infertility: A Possible Role of Gene-Environment Interactions. International journal of environmental research and public health. 2015;12(9):11101-16.
23.Zeliger HI. Exposure to lipophilic chemicals as a cause of neurological impairments, neurodevelopmental disorders and neurodegenerative diseases. Interdisciplinary toxicology. 2013;6(3):103-10.
24.Le Magueresse-Battistoni B, Labaronne E, Vidal H, Naville D. Endocrine disrupting chemicals in mixture and obesity, diabetes and related metabolic disorders. World journal of biological chemistry. 2017;8(2):108-19.
25.Robinson L, Miller R. The Impact of Bisphenol A and Phthalates on Allergy, Asthma, and Immune Function: a Review of Latest Findings. Current environmental health reports. 2015;2(4):379-87.
26.COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD CPATEC. NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES) - INTRODUCTION 2010
27.Takayuki Nakahama YIaMF. Comparative Study on in vitro Inhibitory Effects of Heavy Metals on Rabbit Drug-Metabolizing Enzymes. Journal of Health Science. 2001;47(1):14–20.
28.Bruschweiler BJ, Wurgler FE, Fent K. Inhibitory effects of heavy metals on cytochrome P4501A induction in permanent fish hepatoma cells. Archives of environmental contamination and toxicology. 1996;31(4):475-82.
29.Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Experientia supplementum (2012). 2012;101:133-64.
30.Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y. Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. European journal of endocrinology. 2001;145(4):513-7.
31.Niwa T, Fujimoto M, Kishimoto K, Yabusaki Y, Ishibashi F, Katagiri M. Metabolism and interaction of bisphenol A in human hepatic cytochrome P450 and steroidogenic CYP17. Biological & pharmaceutical bulletin. 2001;24(9):1064-7.
32.Jaeg JP, Perdu E, Dolo L, Debrauwer L, Cravedi JP, Zalko D. Characterization of new bisphenol a metabolites produced by CD1 mice liver microsomes and S9 fractions. Journal of agricultural and food chemistry. 2004;52(15):4935-42.
33.Ginsberg G, Rice DC. Does rapid metabolism ensure negligible risk from bisphenol A? Environmental health perspectives. 2009;117(11):1639-43.
34.Fay MJ, Nguyen MT, Snouwaert JN, Dye R, Grant DJ, Bodnar WM, et al. Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family. Drug Metab Dispos. 2015;43(12):1838-46.
35.Shmarakov IO, Borschovetska VL, Blaner WS. Hepatic Detoxification of Bisphenol A is Retinoid-Dependent. Toxicological sciences : an official journal of the Society of Toxicology. 2017;157(1):141-55.
36.Koch HM, Calafat AM. Human body burdens of chemicals used in plastic manufacture. Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2009;364(1526):2063-78.
37.Frederiksen H, Skakkebaek NE, Andersson A-M. Metabolism of phthalates in humans. 2007;51(7):899-911.
38.Takeshita A, Igarashi-Migitaka J, Nishiyama K, Takahashi H, Takeuchi Y, Koibuchi N. Acetyl Tributyl Citrate, the Most Widely Used Phthalate Substitute Plasticizer, Induces Cytochrome P450 3A through Steroid and Xenobiotic Receptor. Toxicological Sciences. 2011;123(2):460-70.
39.Stein TP, Schluter MD, Steer RA, Ming X. Autism and phthalate metabolite glucuronidation. Journal of autism and developmental disorders. 2013;43(11):2677-85.
40.Walter J. Crinnion JEP. Clinical Environmental Medicine. Identification and Natural Treatment of Diseases Caused by Common Pollutants. Elsevier; 2018 April 26. p. 97.
41.Phthalate NRCUCotHRo. Phthalates and Cumulative Risk Assessment: The Tasks Ahead.: National Academies Press; 2008.
42.Marinkovic N, Pasalic D, Ferencak G, Grskovic B, Stavljenic Rukavina A. Dioxins and human toxicity. Arhiv za higijenu rada i toksikologiju. 2010;61(4):445-53.
43.Schrenk D. Impact of dioxin-type induction of drug-metabolizing enzymes on the metabolism of endo- and xenobiotics. Biochemical pharmacology. 1998;55(8):1155-62.
44.Kubota A, Watanabe MX, Kim EY, Yoneda K, Tanabe S, Iwata H. Accumulation of dioxins and induction of cytochrome P450 1A4/1A5 enzyme activities in common cormorants from Lake Biwa, Japan: temporal trends and validation of national regulation on dioxins emission. Environ Pollut. 2012;168:131-7.
45.Harrad S. Persistent Organic Pollutants: Environmental Behaviour and Pathways of Human Exposure Harrad S, editor. West Sussex, United Kingdom: Chichester; 2001 Edition, .
46.Daidoji T, Gozu K, Iwano H, Inoue H, Yokota H. UDP-GLUCURONOSYLTRANSFERASE ISOFORMS CATALYZING GLUCURONIDATION OF HYDROXY-POLYCHLORINATED BIPHENYLS IN RAT. 2005;33(10):1466-76.
47.Odell GB, Mogilevsky WS, Smith PB, Fenselau C. Identification of glutathione conjugates of the dimethyl ester of bilirubin in the bile of Gunn rats. Molecular pharmacology. 1991;40(4):597-605.
48.Dhakal K, He X, Lehmler H-J, Teesch LM, Duffel MW, Robertson LW. Identification of sulfated metabolites of 4-chlorobiphenyl (PCB3) in the serum and urine of male rats. Chemical research in toxicology. 2012;25(12):2796-804.
49.Bank PA, Salyers KL, Zile MH. Effect of tetrachlorodibenzo-p-dioxin (TCDD) on the glucuronidation of retinoic acid in the rat. Biochimica et biophysica acta. 1989;993(1):1-6.
50.Tarloff J.B. GRS, Hook J.B. Xenobiotic Metabolism in the Mammalian Kidney. Bach P.H. LEA, editor: Springer, Dordrecht; 1987.
51.Makino N, Oyama J-i, Maeda T, Koyanagi M, Higuchi Y, Tsuchida K. Calorie restriction increases telomerase activity, enhances autophagy, and improves diastolic dysfunction in diabetic rat hearts. Molecular and cellular biochemistry. 2015;403(1-2):1-11.
52.Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain research reviews. 2009;59(2):293-315.
53.Chang I-M. Juzen-taiho-to (Shi-Quan-Da-Bu-Tang): Scientific Evaluation and Clinical Application. Evidence-based Complementary and Alternative Medicine. 2006;3(3):393-4.
54.Anjiki N, Hoshino R, Ohnishi Y, Hioki K, Irie Y, Ishige A, et al. A kampo formula Juzen-taiho-to induces expression of metallothioneins in mice. 2005;19(10):915-7.
55.Wu Q, Zhang D, Tao N, Zhu QN, Jin T, Shi JS, et al. Induction of Nrf2 and metallothionein as a common mechanism of hepatoprotective medicinal herbs. Am J Chin Med. 2014;42(1):207-21.
56.Mohamed L Ashour FSY, Haidy A Gad, Michael Wink2. Inhibition of Cytochrome P450 (CYP3A4) Activity by Extracts from 57 Plants Used in Traditional Chinese Medicine (TCM). Pharmacogn Mag. 2016.
57.Kawaguchi-Suzuki M, Frye RF, Zhu H-J, Brinda BJ, Chavin KD, Bernstein HJ, et al. The effects of milk thistle (Silybum marianum) on human cytochrome P450 activity. Drug metabolism and disposition: the biological fate of chemicals. 2014;42(10):1611-6.
58.Polyak SJ, Morishima C, Lohmann V, Pal S, Lee DYW, Liu Y, et al. Identification of hepatoprotective flavonolignans from silymarin. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(13):5995-9.
59.Kim YC, Na JD, Kwon DY, Park JH. Silymarin prevents acetaminophen-induced hepatotoxicity via up-regulation of the glutathione conjugation capacity in mice. Journal of Functional Foods. 2018;49:235-40.
60.Yu T, Chen X, Wang Y, Zhao R, Mao S. Modulatory effects of extracts of vinegar-baked Radix Bupleuri and saikosaponins on the activity of cytochrome P450 enzymes in vitro. Xenobiotica; the fate of foreign compounds in biological systems. 2014;44(10):861-7.
61.Quintieri L, Palatini P, Nassi A, Ruzza P, Floreani M. Flavonoids diosmetin and luteolin inhibit midazolam metabolism by human liver microsomes and recombinant CYP 3A4 and CYP3A5 enzymes. Biochemical pharmacology. 2008;75(6):1426-37.
62.Gebhardt R. Antioxidative and protective properties of extracts from leaves of the artichoke (Cynara scolymus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes. Toxicology and applied pharmacology. 1997;144(2):279-86.
63.Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. Repeated administration of berberine inhibits cytochromes P450 in humans. European journal of clinical pharmacology. 2012;68(2):213-7.
64.Lao-ong T, Chatuphonprasert W, Nemoto N, Jarukamjorn K. Alteration of hepatic glutathione peroxidase and superoxide dismutase expression in streptozotocin-induced diabetic mice by berberine. Pharmaceutical biology. 2012;50(8):1007-12.
65.Muhammad I, Wang H, Sun X, Wang X, Han M, Lu Z, et al. Dual Role of Dietary Curcumin Through Attenuating AFB(1)-Induced Oxidative Stress and Liver Injury via Modulating Liver Phase-I and Phase-II Enzymes Involved in AFB(1) Bioactivation and Detoxification. Frontiers in pharmacology. 2018;9:554-.
66.Krishnaswamy K, Goud VK, Sesikeran B, Mukundan MA, Krishna TP. Retardation of experimental tumorigenesis and reduction in DNA adducts by turmeric and curcumin. Nutrition and cancer. 1998;30(2):163-6.
67.Jagatha B, Mythri RB, Vali S, Bharath MM. Curcumin treatment alleviates the effects of glutathione depletion in vitro and in vivo: therapeutic implications for Parkinson's disease explained via in silico studies. Free radical biology & medicine. 2008;44(5):907-17.
68.NFE2L2protein that regulates the expression of antioxidant proteins. Wikipedia2018.
69.Muhammad I, Wang H, Sun X, Wang X, Han M, Lu Z, et al. Dual Role of Dietary Curcumin Through Attenuating AFB1-Induced Oxidative Stress and Liver Injury via Modulating Liver Phase-I and Phase-II Enzymes Involved in AFB1 Bioactivation and Detoxification. Front Pharmacol. 2018;9:554.