MedChem Drug-Induced Liver Injury

Guang Fang Ji v. Han Fang Ji

-Hundreds of women taking a weight loss supplement Stephania tetranda, or Han Fang Ji

-Several developed renal fibrosis/failure, also cases of microinvasive urothelial carcinomas

-Supplement was mistakenly replaced with Aristolochia fangchi or GuangFang Ji

the birthworts (Aristolochia)

-Long history of use in herbal remedies, especially in birthing

-May be responsible for higher rates of liver cancer in East Asia

Dehydropyrrolizidine (DHP) Alkaloids

-Hepatotoxins, can be, depending on the exact compound, extremely hepatoxic

-Common safety guidelines suggest daily consumption below 7 ng/kg

-FDA requested removal of comfrey from herbal/natural supplements

herbal toxins

-Plants with traditional or purported medical use

-Now known to contain toxins

• e.g. DHP's

• e.g. teucrin A

-Many products banned

• e.g. Birthworts in Taiwan

• e.g. Comfrey in US

Comfrey (Symphytum officinale)

• Used to heal wounds, sprains, fractures

• Established hepatotoxicity

• Contains pyrrolizidine alkaloids

• Banned in the US

Chaparral and Creosote [Larrea sp. (divaticata and tridentate)]

• N. American desert shrubs

• Leaves used for tea

• Used to treat a variety of maladies

• Contains powerful antioxidant

• Nordihydroguaiaretic acid forms reactive ortho-quinones

• Multiple cases of liver damage

Germander (Teucrium lamiceae)

• Aromatic plant in mint family

• Leaves used for tea

• Used for weight loss, diabetes, and hyperlipidemia

• Teucrin A is hepatotoxic diterpene

• Multiple cases of liver injury (severe & fatal)

Greater Celandine (Chelidonium majus)

• Used for digestive problems

• Drug development efforts showed no evidence for effectiveness

• Produce diverse isoquinoline alkaloids

• Many cases of liver toxicity and jaundice

Penny Royal (Menta pulegium)

• Extract or essential oil

• Plant in mint family

• Used as abortifacient

• High concentrations of pulegone

• Highly toxic and liver toxic

• Many reported cases (severe & death)

Kava Kava (Piper methysticum)

• Shrub in Pacific Islands

• Rhizomes and roots are steeped in hot water or coconut milk

• Used for anxiety and fatigue

• Contains kavalactones

• Risk of severe liver disease

Skullcap (Scutellaria lateriflora)

• American plant

• Leaves brewed as tea

• Used for anxiety, stress, and insomnia

• Commonly adulterated with hepatotoxic germander (teucrin A)

adulteration in supplements

-When a valuable ingredient has been omitted in part, whole, replaced (spiked), or contaminated.

Examples:

- Belgian cases: Guang Fang ji vs. Han Fang ji

- Skullcap adulteration with germander

common

The risk of adulteration with plant toxins is __________

compounds of concern

arisotlic acids (carcinogen) and dehydropyrrolizidines (liver toxins)

autoimmune injuries

-errant stimulation of the immune system

-Occur when enzyme-drug adducts migrate to cell surface and form an antigen

-Think about what structures can adduct to enzymes/proteins

-N-N single bonds will be common

-liver hosts many immune cells

Halothane (Fluothane®)

General anesthetic

• Hepatotoxic

• Metabolized by CYP2E1 to acid chloride

• Metabolites create antigens at cell surface

oxidation leads to a reactive acid chloride

What sort of chemistry could we draw to react Halothane with a CYP enzyme?

sulfamethoxazole/Trimethoprim (Bactrim)

Sulfonamide antibiotic (bacterial folic acid synthesis inhibitor)

• Hepatotoxic

• Also causes cholestatic jaundice

• CYP450 hydroxylation of aniline creates toxic metabolite

Dantrolene (Dantrium)

Skeletal muscle relaxant

• Associated with chronic active hepatitis

• Nitrogen-nitrogen bond is structural feature for hepatotoxicity

hepatotoxicity

What is the BBW for Dantrolene (Dantrium)?

N-N triple bonds

near unbreakable, no metabolism in our bodies

N-N double bonds

strong, need special gut microbes to break

N-N single bond

labile, often hepatotoxic (MOA not well understood)

Isoniazid (Hydra®)

Anti-infective (for tuberculosis)

• Associated with chronic active hepatitis

• Nitrogen-nitrogen bond is structural feature for hepatotoxicity

hepatotoxicity

What is the BBW for Isoniazid (Hydra)?

Nitrofurantoin (Macrobid®)

Anti-infective (inhibits ribosomal protein synthesis)

• Associated with chronic active hepatitis

• Nitrogen-nitrogen bond is structural feature for hepatotoxicity

Phenytoin (Dilantin®)

Anti-convulsant

• Associated with chronic active hepatitis

• CYP450-mediated oxidation of benzene rings produces reactive

intermediate

idiosyncratic reactions

-rare

-categorized as allergic or non-allergic reactions

allergic reactions

produce fever, rash, eosinophilia, and hepatotoxicity with rapid onset

non-allergic reactions

do not produce hypersensitivity response but have long latency (about 6 months)

Amoxicillin/clavulanic acid (Augmentin®)

Antibiotic (beta-lactamase inhibitor)

• Allergic reaction from clavulanic acid

• Rare, usually in elderly patients

• Severe hepatic dysfunction, but reversible

Bactrim, phenytoin, and macrobid

What are the compounds that cause allergic reactions?

isoniazid (Hydra)

What is a compound that causes a non-allergic reaction?

Ketoconazole (Nizoral)

anti-fungal agent

-causes non-allergic reaction

hepatotoxicity

What is the BBW with Ketoconazole (Nizoral)?

Amiodarone (Cardarone)

Class III anti-arrhythmic agent

• Causes non-allergic reaction

• Hepatotoxicity associated with intravenous formulation

• Toxicity rare

hepatotoxicity

What is the BBW of Amiodarone?

toxicity from CYP450 enzymes

-highly reactive drug metabolites are produced in the liver by these

-reactive metabolites form covalent bonds with cellular proteins and DNA

-lead to liver cell injury or cell lysis

-acute toxicity is observed

Acetaminophen (Tylenol)

• CYP450 hydroxylation of amide creates toxic metabolite

• Liver damage may result from acute high dose or chronic usage

• Can cause acute liver failure

• Common OTC medicine

quinoneimine

Tylenol is activated by oxidation which leads to reactive _____________

liver tox

Depletion of glutathione with Tylenol leads to ___________

N-actylcysteine

has a free thiol and is the antidote for Tylenol tox

Diclofenac (Voltaren®)

• Liver damage may result from acute high dose or chronic usage

• Less prevalent

• Two CYP450 hydroxylations create toxic metabolite

inhibition of transporters

• Liver transport proteins are efflux pumps

• Inhibition of these transporters causes accumulation of drugs, metabolites, and xenobiotics

• Can affect liver and bile

• Also observed from genetic disorders

mitochondrial injury

• Drugs affect the mitochondrial structure

• Mechanism can block beta-oxidation of lipids or disrupt oxidative phosphorylation

• Severe damage leads to hepatic cell injury and cell death

• Can present as acute disorder or chronic disorder

-Aspirin

-Tetracycline

-Valproic Acid

-Amiodarone

What drugs cause mitochondrial injury?

L-carnitine

What is the reversal agent of Valproic acid?

-Omission of a key ingredient

-Spiking of drugs/dangerous ingredients (e.g. birthworts with aristolochic acid)

-Contamination

-Unknown interactions with off label ingredients

What are the risks of adulteration with herbal supplements?

aristolochic acid and dehydroprrolizidines

What are the common plant hepatotoxins?

aristolochic acid

-Found in the birthworts (Arisolochia)

-Chemical mutagen can lead to cancer

Dehydroprrolizidines

found widely across the flowering plants, can contaminate other herbs

-Patients may under-report/not report use

-Patients believe them to be safe/not consult with medical team about use

-Risk of adulteration

What are the risks with herbal supplements?

-autoimmune injuries

-idiosyncratic reactions

-toxicity through CYPs

-inhibition of transporters

-mitochondrial injury

What are the different pathways that the liver is harmed/disrupted?

autoimmune injuries

presentation of protein-drug conjugates on the cell surface leads to an immune response and destruction of the cell

idiosyncratic reactions

rare complications of drug use that can be allergic or non-allergic, happen at prescribed doses

toxicity through CYP enzymes

oxidative chemistry converts drugs to reactive toxins

mitochondiral injury

damage to the mitochondria leas to cells stress and death

The birthworts (Aristolochia)

Class: Hepatoxic herbs (Purported aid in birthing)

Known Toxin: Aristolochic acid

Notes: Used in traditional Chinese medicine (Guang Fang ji), partial ban in Taiwan

Comfrey Symphtum officinale

Class: Hepatoxic herbs (Purported wound treatment, healing effects)

Known Toxin: dehydroprrolizidines

Notes: Banned in US herbal supplements

Chaparral and Creosote Larrea divaticata and Larrea tridentate

Class: Hepatoxic herbs (Traditional Native American/Mexican usage for a variety of remedies)

Known Toxin: nordihydrogualaretic acid

Notes: Oxidized to reactive orthoquinones

Germander Teucrium lamiaceae

Class: Hepatoxic herbs (Use as a weight loss supplement)

Known Toxin: teucrin A

Notes: Multiple cases of severe/fatal injury

Greater Celandine Chelidonium majus

Class: Hepatoxic herbs (Use for digestive properties)

Known Toxin: coptisine and other isoquinoline alkaloids

Notes: Dropped from drug development activities

Penny Royal Mentha pulegium

Class: Hepatoxic herbs (Use as abortifacient)

Known Toxin: pulegone

Notes: Highly toxic

Kava kava Piper methysticum

Class: Hepatoxic herbs (Use for stress relief and fatigue)

Known Toxin: kavalactones

Notes: From the Pacific islands

Skullcap Scutellaria lateriflora

Class: Hepatoxic herbs (Use for anxiety, stress, and insomnia)

Known Toxin: Not actually toxic, but commonly contaminated with germander

Notes: American plant

Halothane (Fluothane®)

Class: General anesthetic

Mechanism of Liver Toxicity: Autoimmune Injury - Oxidation and then loss of HBr leads to acid chloride then protein-

trifluoroacetate conjugates

Notes: Oxidation through CUP2E1

Trimethoprim/sulfamethoxazole (Bactrim®)

Class: Sulfonamide antibiotics

Mechanism of Liver Toxicity: Autoimmune Injury/Idiosyncratic (allergic) - Hydroxylation of alinine lead to toxic metabolite

Notes: Oxidation through CYP450 enzymes

Dantrolene (Dantrium®)

Class: Skeletal muscle relaxant

Mechanism of Liver Toxicity: Autoimmune Injury

FDA BOX WARNING: Hepatotoxicity

Notes: Associated with chronic active hepatitis

Isoniazid (Hydra®)

Class: Anti-infective (Tuberculosis)

Mechanism of Liver Toxicity: Autoimmune Injury/Idiosyncratic (non-allergic)

FDA BOX WARNING: Hepatotoxicity

Notes: Associated with chronic active hepatitis

Nitrofurantoin (Macrobid®)

Class: Anti-infective

Mechanism of Liver Toxicity: Autoimmune Injury/Idiosyncratic (allergic)

Notes: Associated with chronic active hepatitis

Phenytonin (Dilantin®)

Class: Anti-convulsant

Mechanism of Liver Toxicity: Autoimmune Injury/Idiosyncratic (allergic)

Notes: Through CYP450 processing

Ketoconazole (Nizoral®)

Class: Anti-fungal

Mechanism of Liver Toxicity: Idiosyncratic (non-allergic)

FDA BOX WARNING: Hepatotoxicity

Amiodarone (Pacerone®)

Class: Anti-arrhythmic (Class III)

Mechanism of Liver Toxicity: Acute hepatotoxicity with IV administration, chronic toxicity can be cirrhosis or sometimes

cholestasis.

FDA BOX WARNING: Hepatotoxicity

Notes: Disruption of mitochondrial oxidative phosphorylation also observed.

Acetominophen (Tylenol®)

Class: Pain relief

Mechanism of Liver Toxicity: CYP450 Toxicity (through quinoenimine)

Notes: Causes the majority of drug-induced liver injury

N-acetylcysteine (Acetadote®)

Class: Antidote for acetaminophen overdose

Notes: Also a formulation for oral mist (Mucomyst®), where the free thiol breaks down disulfide crosslinks in mucosal proteins.

Diclofenac (Voltaren®)

Class: NSAID

Mechanism of Liver Toxicity: CYP450 Toxicity (through quinoenimine)

Notes: Need two CYP450 oxidations in this case, but then mechanism is the same as acetaminophen

Cyclosporin (SandImmune®)

Class: Immunosuppressant

Mechanism of Liver Toxicity: Transporter Inhibition (Bile Salt Export Pump)

Notes: Usually associated with high doses

Rifamycin (Aemcolo®)

Class: Antibiotic

Mechanism of Liver Toxicity: Transporter Inhibition (Bile Salt Export Pump)

Notes: Hepatotoxicity is rare

Sulindac (Clinoril®)

Class: NSAID

Mechanism of Liver Toxicity: Transporter Inhibition (Bile Salt Export Pump)

Notes: Hepatotoxicity is rare, elevation of transaminases is a warning sign

Acetylsalicylic acid (Asprin®)

Class: NSAID

Mechanism of Liver Toxicity: Mitochondrial Injury

Notes: Avoid in cases of hepatic function impairment

Tetracycline (Sumycin®)

Class: Antibiotic

Mechanism of Liver Toxicity: Mitochondrial Injury

Notes: Hepatotoxicity is rare

Valproic acid (Depakene®)

Class: Anticonvulsant

Mechanism of Liver Toxicity: Mitochondrial Injury

FDA BOX WARNING: Hepatotoxicity

Notes: Associated acute hepatic failure

L-carnitine

Class: Antidote for Valproic acid toxicity

Mechanism of Liver Protection: Essential metabolite for mitochondrial activity, can be depleted during liver injury, thus

supplementation thought to be protective.

Notes: A metabolite produced by our own metabolism and adsorbed from diet (commonly meat), used to aid fatty acid

membrane transport by mitochondria.