Hepatotoxicity
Hepatotoxicity (from hepatic toxicity) implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.
The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses (e.g. paracetamol) and sometimes even when introduced within therapeutic ranges (e.g. halothane), may injure the organ. Other chemical agents, such as those used in laboratories and industries, natural chemicals (e.g., microcystins), and herbal remedies (two prominent examples being kava, mechanism unknown, and comfrey, through its pyrrolizidine alkaloid content) can also induce hepatotoxicity. Chemicals that cause liver injury are called hepatotoxins.
More than 900 drugs have been implicated in causing liver injury (see LiverTox, external link, below) and it is the most common reason for a drug to be withdrawn from the market. Hepatotoxicity and drug-induced liver injury also account for a substantial number of compound failures, highlighting the need for toxicity prediction models (e.g. DTI), and drug screening assays, such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process. Chemicals often cause subclinical injury to the liver, which manifests only as abnormal liver enzyme tests.
Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures.

Causes
Adverse drug reactions are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic). Type A drug reaction accounts for 80% of all toxicities.Drugs or toxins that have a pharmacological (type A) hepatotoxicity are those that have predictable dose-response curves (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity, such as directly damaging liver tissue or blocking a metabolic process. As in the case of paracetamol overdose, this type of injury occurs shortly after some threshold for toxicity is reached. Carbon tetrachloride is commonly used to induce acute type A liver injury in animal models.
Idiosyncratic (type B) injury occurs without warning, when agents cause non-predictable hepatotoxicity in susceptible individuals, which is not related to dose and has a variable latency period. This type of injury does not have a clear dose-response nor temporal relationship, and most often does not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process; Troglitazone (Rezulin) and trovafloxacin (Trovan) are two prime examples of idiosyncratic hepatotoxins pulled from market.
The herb kava has caused a number of cases of idiosyncratic liver injury, ranging everywhere from asymptomatic to fatal.
Oral use of the antifungal ketoconazole has been associated with hepatic toxicity, including some fatalities; however, such effects appear to be limited to doses taken over a period longer than 7 days.

Paracetamol
Paracetamol also known as acetaminophen, and by the brand names of Tylenol and Panadol, is usually well-tolerated in prescribed dose, but overdose is the most common cause of drug-induced liver disease and acute liver failure worldwide.  Damage to the liver is not due to the drug itself but to a toxic metabolite (N-acetyl-p-benzoquinone imine (NAPQI)) produced by cytochrome P-450 enzymes in the liver. In normal circumstances, this metabolite is detoxified by conjugating with glutathione in phase 2 reaction. In an overdose, a large amount of NAPQI is generated, which overwhelms the detoxification process and leads to liver cell damage.   Nitric oxide also plays a role in inducing toxicity. The risk of liver injury is influenced by several factors including the dose ingested, concurrent alcohol or other drug intake, interval between ingestion and antidote, etc. The dose toxic to the liver is quite variable from person to person and is often thought to be lower in chronic alcoholics. Measurement of blood level is important in assessing prognosis, higher levels predicting a worse prognosis. Administration of Acetylcysteine, a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI. Those that develop acute liver failure can still recover spontaneously,  but may require transplantation if poor prognostic signs such as encephalopathy or coagulopathy is present (see Kings College Criteria).

Nonsteroidal anti-inflammatory drugs
Although individual analgesics rarely induce liver damage due to their widespread use, NSAIDs have emerged as a major group of drugs exhibiting hepatotoxicity. Both dose-dependent and idiosyncratic reactions have been documented. Aspirin and phenylbutazone are associated with intrinsic hepatotoxicity; idiosyncratic reaction has been associated with ibuprofen, sulindac,  phenylbutazone, piroxicam, diclofenac and indomethacin.

Glucocorticoids
Glucocorticoids are so named due to their effect on the carbohydrate mechanism. They promote glycogen storage in the liver. An enlarged liver is a rare side-effect of long-term steroid use in children. The classical effect of prolonged use both in adult and paediatric population is steatosis.

Isoniazid
Isoniazide (INH) is one of the most commonly used drugs for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1-2% of patients.

Other hydrazine derivative drugs
There are also cases where other hydrazine derivative drugs, such as the MAOI antidepressant iproniazid, are associated with liver damage. Phenelzine has been associated with abnormal liver tests. Toxic effects can develop from antibiotics.

Natural products
Examples include alpha-Amanitin containing mushrooms, kava, and aflatoxin producing molds. Pyrrolizidine alkaloids, which occur in some plants, can be toxic. Green tea extract is a growing cause of liver failure due to its inclusion in more products.

Alternative remedies
Examples include: Ackee fruit, Bajiaolian, Camphor, Copaltra, Cycasin, Garcinia, Kava leaves, pyrrolizidine alkaloids, Horse chestnut leaves, Valerian, Comfrey. Chinese herbal remedies: Jin Bu Huan, Ephedra, Shou Wu Pian, Bai Xian Pi.

Industrial toxin
Examples include arsenic, carbon tetrachloride, and vinyl chloride.

Mechanism
Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and the spleen via portal veins that bring drugs and xenobiotics in near-undiluted form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process.
Many chemicals damage  mitochondria, an intracellular organelle that produces energy. Its dysfunction releases excessive amount of oxidants that, in turn, injure hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as  CYP2E1 also lead to oxidative stress. Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside the liver. This promotes further liver damage. Non-parenchymal cells such as Kupffer cells, collagen-producing stellate cells, and leukocytes (i.e. neutrophil and monocyte) also have a role in the mechanism.

Drug metabolism in liver
The human body subjects most, but not all, compounds to various chemical processes (i.e. metabolism) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissues in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in the liver is the principal "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones,  fatty acids, proteins) and exogenous substances (e.g., drugs, alcohol). The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury.
Drug metabolism is usually divided into two phases: phase 1 and phase 2. Phase 1 reaction is generally speaking to prepare a drug for phase 2. However, many compounds can be metabolized by phase 2 directly or be excreted without any phase 2 reactions occurring. Phase 1 reaction involves oxidation, reduction, hydrolysis, hydration and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites that are more chemically active and/or potentially toxic. Most of phase 2 reactions take place in  cytosol and involve conjugation with endogenous compounds via transferase enzymes. Phase 1 are typically more suitable for elimination.
A group of enzymes located in the endoplasmic reticulum, known as cytochrome P-450, is the most important family of metabolizing enzymes in the liver. Cytochrome P-450 is not a single enzyme, but rather consists of a closely related family of 50 isoforms; six of them metabolize 90% of drugs. There is a tremendous diversity of individual P-450 gene products, and this heterogeneity allows the liver to perform oxidation on a vast array of chemicals (including most drugs) in phase 1. Three important characteristics of the P-450 system have roles in drug-induced toxicity:

1. Genetic diversity:Each of the P-450 proteins is unique and accounts (to some extent) for the variation in drug metabolism between individuals. Genetic variations (polymorphism) in P-450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. Such polymorphism is also responsible for variable drug response among patients of differing ethnic backgrounds.

2. Change in enzyme activity:Many substances can influence the P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways. Drugs that modify cytochrome P-450 enzyme are referred to as either inhibitors or inducers. Enzyme inhibitors block the metabolic activity of one or several P-450 enzymes. This effect usually occurs immediately. On the other hand, inducers increase P-450 activity by increasing enzyme production, or, in the case of CYP2E1, preventing degradation in the proteasome. There is usually a delay before enzyme activity increases.
3. Competitive inhibition:Some drugs may share the same P-450 specificity and thus competitively block their biotransformation. This may lead to accumulation of drugs metabolized by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic metabolites.

Patterns of injury
Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (e.g. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as a rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP. Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed types of injuries are often encountered.
Specific histo-pathological patterns of liver injury from drug-induced damage are discussed below.

Zonal Necrosis
This is the most common type of drug-induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule. It may manifest as a very high level of ALT and severe disturbance of liver function leading to acute liver failure.

Causes include:
Paracetamol, carbon tetrachloride

Hepatitis
In this pattern, hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug-induced hepatitis. (A) viral hepatitis is the most common, where histological features are similar to acute viral hepatitis. (B) in focal or non-specific hepatitis, scattered foci of cell necrosis may accompany lymphocytic infiltration. (C) chronic hepatitis is very similar to autoimmune hepatitis clinically, serologically, and histologically.

Causes:
(a) Viral hepatitis: Halothane, isoniazid, phenytoin
(b) Focal hepatitis: Aspirin
(c) Chronic hepatitis: Methyldopa, diclofenac

Cholestasis
Liver injury leads to impairment of bile flow and cases are predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland (without any parenchymal inflammation). On rare occasions, it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (vanishing duct syndrome).

Causes:
(a) Bland: Oral contraceptive pills, anabolic steroid, androgens
(b) Inflammatory: Allopurinol, co-amoxiclav, carbamazepine
(c) Ductal: Chlorpromazine, flucloxacillin

Steatosis
Hepatotoxicity may manifest as triglyceride accumulation, which leads to either small-droplet (microvesicular) or large-droplet (macrovesicular) fatty liver. There is a separate type of steatosis by which phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g., Tay–Sachs disease)

Causes:
(a) Microvesicular: Aspirin (Reyes syndrome), ketoprofen, tetracycline (especially if expired)
(b) Macrovesicular: Acetaminophen, methotrexate
(c) Phospholipidosis: Amiodarone, total parenteral nutrition
(d) Antiviral: nucleoside analogues
(e) Corticosteroid
(f) Hormonal: Tamoxifen

Granuloma
Drug-induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated.

Causes:
Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine

Vascular lesions
These result from injury to the vascular endothelium.

Causes:
Venoocclusive disease: Chemotherapeutic agents, bush tea
Peliosis hepatis: Anabolic steroids
Hepatic vein thrombosis: Oral contraceptives

Neoplasm
Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma, and liver adenomas are the ones usually reported.

Causes:
Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast

Diagnosis
This remains a  challenge in clinical practice due to a lack of reliable markers. Many other conditions lead to similar clinical as well as pathological pictures. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected. Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established, dose-dependent, pharmacological hepatotoxicity is easier to spot. Several clinical scales such as CIOMS/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. CIOMS/RUCAM scale involves a scoring system that categorizes the suspicion into "definite or highly probable" (score > 8), "probable" (score 6–8), "possible" (score 3–5), "unlikely" (score 1–2) and "excluded" (score ≤ 0). In clinical practice, physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity (e.g., cholestatic damage in  amoxycillin-clauvonic acid ).

Treatment
In most cases, liver function will return to normal if the offending drug is stopped early. Additionally, the patient may require supportive treatment. In acetaminophen toxicity, however, the initial insult can be fatal. Fulminant hepatic failure from drug-induced hepatotoxicity may require liver transplantation. In the past, glucocorticoids in allergic features and ursodeoxycholic acid in cholestatic cases had been used, but there is no good evidence to support their effectiveness.

Prognosis
An elevation in serum bilirubin level of more than 2 times ULN with associated transaminase rise is an ominous sign. This indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped (Hys Law). This is because it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or Gilbert syndrome) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high AST.

Drugs withdrawn
The following therapeutic drugs were withdrawn from the market primarily because of hepatotoxicity: Troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, ximelagatran and pemoline.

See also
Hepatoprotection
Reyes syndrome

Notes
References
Friedman, Scott E.; Grendell, James H.; McQuaid, Kenneth R. (2003). Current diagnosis & treatment in gastroenterology. New York: Lang Medical Books/McGraw-Hill. pp. 664–679. ISBN 978-0-8385-1551-8.
Dixit, Vaibhav A. (2019). "A simple model to solve a complex drug toxicity problem". Toxicology,Research. 8 (2):157171. doi:10.1039/C8TX00261D. PMC 6417485. PMID 30997019.
Ostapowicz G, Fontana RJ, Schiødt FV, et al. (2002). "Results of a prospective study of acute liver failure at 17 tertiary care centres in the United States". Ann. Intern. Med. 137 (12).947–54. doi:10.7326/0003-4819-1371220021217000007. PMID 12484709. S2CID 11390513.
Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK (1998). "Adverse drug reactions". BMJ. 316 (7140):12958. doi:10.1136/bmj.316.7140.1295. PMC 1113033. PMID 9554902.
Manov I, Motanis H, Frumin I, Iancu TC (2006). "Hepatotoxicity of anti-inflammatory and analgesic drugs: ultrastructural aspects". Acta Pharmacol. Sin. 27 (3): 259–72. doi:10.1111/j.1745-7254.2006.00278.x. PMID 16490160. S2CID 26874901.
Alpers DH, Sabesin SM (1982). Schiff L; Schiff ER (eds.). Diseases of the liver. Philadelphia: JB Lippincott. pp. 813–45
Chalasani, Naga P.; Hayashi, Paul H.; Bonkovsky, Herbert L.; Navarro, Victor J.; Lee, William M.; Fontana, Robert J.; Practice Parameters Committee of the American College of Gastroenterology (2014). "ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury". The American Journal of Gastroenterology. 109 (7):950966. doi:10.1038/ajg.2014.131. PMID 24935270. S2CID 2417493
Patel T, Roberts LR, Jones BA, Gores GJ (1998). "Dysregulation of apoptosis as a mechanism of liver disease: an overview". Semin. Liver Dis. 18 (2): 105–14. doi:10.1055/s-2007-1007147. PMID 9606808
Mumoli N, Cei M, Cosimi A (2006). "Drug-related hepatotoxicity". N. Engl. J. Med. 354 (20):21913,author,reply21913. doi:10.1056/NEJMc060733. PMID 16710915
Bénichou C (1990). "Criteria of drug-induced liver disorders. Report of an international consensus meeting". J. Hepatol. 11 (2): 272–6. doi:10.1016/0168-8278(90)90124-A. PMID 2254635
Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI. (1995) Role of pro‑inflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 1995;133:43‑52
Yadav V, Rai R, Yadav A, Pahuja M, Solanki S, et al. (2012) Evaluation of antibacterial activity of Callicarpa macrophylla Vahl. stem extracts
Siddiqui H (1993) Safety of herbal drugs-an overview. Drugs News Views
Kumar A, Rohal A, Chakraborty S, Tiwari R, Latheef SK, et al. (2013) Ocimum sanctum (Tulsi): a miracle herb and boon to medical science Review. Int J Agron Plant Prod 4: 589
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, et al. (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1
Singh N, Verma P, Pandey BR, Bhalla M (2012) Therapeutic potential of Ocimum sanctum in prevention and treatment of cancer and exposure to radiation: An overview. Int J Pharmacist Sci Drug Res 4: 97–104.
Mondal S, Mirdha BR, Mahapatra SC (2009) The science behind sacredness of Tulsi (Ocimum sanctum Linn.). Indian J Physiol Pharmacol 53: 291–306.
Devra D, Mathur KC, Agrawal RP, Bhadu I, Goyal S, et al. (2012) Effect of Tulsi (Ocimum sanctum Linn.) on Clinical and Biochemical Parameters of Metabolic Syndrome. J Nat Remedies 12: 63-67
Ahmad I, Beg AZ (2001) Antimicrobial and phytochemical studies on 45 Indian medicinal plants against multi-drug resistant human pathogens. Ethnopharmacol 74: 113–123.
Amadi J, Salami S, Eze C (2010) Antifungal properties and phytochemical screening of extracts of African basil (Ocimum gratissimum L.). Agr Biol J North America 1: 163–166.
Ponnusam Y, Louis T, Madhavachandran V, Kumar S, Thoprani N, et al. (2015) Antioxidant Activity of The Ancient Herb, Holy Basil in CCl4-Induced Liver Injury in Rats. Ayurvedic 2: 34–38.
Ravi V, Parida S, Desai A, Chandramukhi A, Devi MG, et al. (1997) Correlation of tumor necrosis factor levels in the serum and cerebrospinal fluid with clinical outcome in Japanese encephalitis patients. J Med Virol 51: 132–136.
Kumari P, Yadav P, Verma PR, Kumar, Arya, Kumar S, et al. (2013) A review on wound healing properties of Indian medicinal plants. Ind J Fund Appl Life Sci 3: 220–232.
Kumar A, Agarwal K, Maurya AK, Shanker K, Bushra U, et al. (2015) Pharmacological and phytochemical evaluation of Ocimum sanctum root extracts for its anti-inflammatory, analgesic and antipyretic activities. Pharmacogn Mag 11: S217.
Ranjana T, Tripathi V (2015) Therapeutic effect of tulsi (Ocimum sanctum Linn) in general and oral health. Ayurlog: National Journal of Research in Ayurveda Science 3: 1–12.
Suanarunsawat T, Ayutthaya WDN, Thirawarapan S, Poungshompoo S (2014) Anti-oxidative, anti-hyperglycemic and lipid-lowering effects of aqueous extracts of Ocimum sanctum L. leaves in diabetic rats. Food Nutr Sci 5: 801–811.
Talekar, Y. P., Das, B., Paul, T., Talekar, D. Y., Apte 1, K. G., & Parab, P. B. (2012). Evaluation of hepatoprotective Potential of Aqueous and Ethanolic Extract of Ocimum sanctum Linn. In Wistar Rats. Asian Journal of Pharmaceutical and Clinical Research, 5(4), 141–145.
Singh V, Kumar R.(2017).Study of Phytochemical Analysis and Antioxidant Activity of Allium sativum of Bundelkhand Region. International Journal of Life Sciences Scientific Research. 3(6):1451-1458.
Raaman N.(2006). Phytochemical Techniques. New India Publishing Agency, New Delhi, 19–24.
Tiwari P, Kumar B, Kaur M, Kaur G, Kaur H.(2011). Phytochemical screening and Extraction: A Review. Internationale Pharmaceutica Sciencia. 1(1):98-106.
Auwal MS, Saka S, Mairiga IA, Sanda KA, Shuaibu A and Ibrahim A.(2014) Preliminary phytochemical and elemental analysis of aqueous and fractionated pod extracts of Acacia nilotica (Thorn mimosa). Veterinary Research Forum.5(2):95-100.
Sadasivam S, Manickam A, Biochemical methods.(2005). Edn 3, New Age International Limited, Publishers, New Delhi. 1–4.
Basumatary AR.(2016).Preliminary Phytochemical Screening of some compounds from plant stem bark extracts of Tabernaemontana divaricata Linn. used by Bodo Community at Kokrajhar District, Assam, India. Archives of Applied Science Research.8(8):47-52
Silva GO, Abeysundara AT, Aponso MM.(2017). Extraction methods, qualitative and quantitative techniques for screening of phytochemicals from plants. American Journal of Essential Oils and Natural Products.5(2):29-32
Jagessar RC.(2017). Phytochemical screening and chromatographic profile of the ethanolic and aqueous extract of Passiflora edulis and Vicia faba L. (Fabaceae). Journal of Pharmacognosy and Phytochemistry.6(6):1714-1721
Gul R, Jan SU, Syed F, Sherani F, Nusrat Jahan.(2017).Preliminary Phytochemical Screening, Quantitative Analysis of Alkaloids, and Antioxidant Activity of Crude Plant Extracts from Ephedra intermedia Indigenous to Balochistan. The Scientific World Journal.1-7
Rubin, E., Hutter, F., Proper, H. (1963). Cell proliferation and fiber formation in chronic carbon tetrachloride intoxication. A morphologic and chemical study. American Journal of Pathology 42, 715.
Recnagal, R. (1983). Carbon tetrachloride hepatotoxicity, status quo and future prospects. Trends in Pharmacological Science 4, 129–131.
Slater, T.F. (1978). Biochemical Studies on Liver Injury. Academic Press, New York, pp. 1–44.
Reitman, S., Frankel, S. (1957). A colorimetric method for the determination of serum glutamate oxaloacetate transaminases. American Journal of Clinical Pathology 28, 56–63.
Malloy, H.T., Evelyn, K.A. (1937). The determination of bilirubin with the photometric colorimeter. Journal of Biological Chemistry 119, 481–490.
Kind, P.R.N., Kings, E.J. (1976). Determination of serum bilirubin. Journal Clinical Pathology 7, 322–330.
Brand-Williams, W.; Cuvelier, M.E.; Berset, C. (1995). Use of a free radical method to evaluate antioxidant activity. LWT—Food Sci. Technol. 28, 25–30.
Shah, N.A.; Khan, M.R.; Ahmad, B.; Noureen, F.; Rashid, U.; Khan, R.A. (2013) Investigation on flavonoid composition and anti-free radical potential of Sida cordata. BMC Complement. Altern. Med, 13, 276.
Zengin, G.; Aktumsek, A.; Guler, G.O.; Cakmak, Y.S.; Yildiztugay, E. (2011). Antioxidant properties of methanolic extract and fatty acid composition of Centaurea urvillei DC. Subsp. Hayekiana Wagenitz. Rec. Nat. Prod., 5, 123–132.
Mitsuda, H.; Yasumoto, K.; Iwami, K. (1966). Antioxidative action of indole compounds during the autooxidation of linoleic acid. Nippon Eiyo Shokuryo Gakkaishi, 19, 210–214
Baccanari, D.; Phillips, A.; Smith, S.; Sinski, D.; Burchall, J. (1975-12-02). "Purification and properties of Escherichia coli dihydrofolate reductase". Biochemistry. 14 (24): 5267–5273. doi:10.1021/bi00695a006. ISSN 0006-2960. PMID 46.

External links

LiverTox at the United States National Library of Medicine