Monoamine oxidase (MAO) is a flavoprotein present in mitochondrial membranes and catalyzes the oxidative deamination of several neurotransmitters (noradrenaline, dopamine, serotonine) to aldehydes. Other enzymes convert the aldehyde to an alcohol or carboxylic acid. MAO catabolizes an excess of the neurotransmitter. The antidepressant action of MAOinhibitors lies in interfering in this process and prolonging the action of the neurotransmitters. MAO-inhibitors are a heterogeneous group of drugs that can be subdivided into a hydrazinederivates such as iproniazid, phenelzine, and pheniprazine and non-hydrazine-based therapeutics such as isocarboxazid and tranylcypromine (TCP) (Table 1). These drugs were the first clinically useful antidepressant drugs and had therefore an important impact on the development of modern biological psychiatry. After 1970, MAO-inhibitors were tarnished because they interact with many drugs and food-derived amines and exert therefore notorious side effects such as hepatic necrosis and hypertensive crises. However, new insights brought selective MAO inhibitors, such as TCP, with lesser side effects back on the market, albeit under strict medical supervision of a psychiatrist. Specifically, TCP is a mechanism-based (or suicide) inhibitor that first interacts reversibly with the enzyme to form a non-covalent complex. Thereafter, the irreversible reaction takes place to form a covalently-bound enzyme-inhibitor adduct: 𝐸 + 𝐼 ⇌ 𝐸𝐼 ⟶ 𝐸𝐼 ∗ This irreversible binding can manifest for 14 days. Tranylcypromine inhibits CYP2A6, CYP2C9, CYP2C19, and CYP2E1. Maximum plasma levels are reached after 0.5-3.5 hours. Primary liver biotransformation products are p-hydroxytranycypromine and n-acetyltranylcypromine. Whereas all metabolites are eliminated within 24 hours after the latest dose, it takes 3-5 days to fully recover the activity of the enzyme MAO because of the irreversible MAOinhibition. Metabolites are eliminated via bile and mainly via the kidneys. Only 4% of its dose is unchanged eliminated via urine as tranylcypromine. *Each of the drugs which has caused jaundice is a derivative of hydrazine, itself a potent hepatotoxic agent in laboratory animals (Yard and McKennis 1955) *TCP has been regarded as a much safer drug than iproniazid, as it is not cumulative. *TCP rarely causes jaundice. There have been 2 cases of hepatocellular damage due to this drug, one reported (Bandt 1964). See also table 2. Toloxatone is also a non-hydrazine monamine oxidase inhibitor. It also has led to at least two cases of hepatocellular injury. Both were fatal. More information TCP: what are the common side-effects? --> Mild gastro-intestinal problems. Prof Gouw (hepatopathologist UMCG) has another book where tranylcypromine is mentioned: MacSween’s Pathology of the liver. She will look into it tomorrow.. Substance N-isoNicotinoyl-Nisopropylhydrazine a-methylphenethylhydrazine Official name Iproniazid Proprietary name Marsilid Pheniprazine N-(2-Benzylcarbamlethyl)-Nisonicotinylhydrazine Phenethylhydrazine Nialamine Cavodil Catron Niamid Phenelzine Nardil Isocarboxazid Tersavid Marplan 1-benzyl-2-pivaloylhydrazine 3-N-Benzylhydrazinecarbonyl-5methylisoxazole Trans (±)-2Phenylcyclopropylamine Table 1. MAO-inhibiting drugs Tranylcypromine Parnate Parstellazine Features of TCP-induced hepatotoxicity Clinical symptoms such as jaundice, malaise, anorexia, and nausea after 1-4 months Serum aminotransferase elevations are hepatocellular Mechanism of aminotransferase elevations unknown, possibly cause is production of a toxic intermediate metabolism. The hepatotoxicity seems to be based on idiosyncrasy. Transient serum aminotransferase elevations in a proportion of patients; usually mild, asymptomatic, selflimiting and does not require dose modification. Rare cases of acute, clinically apparent liver injury These cases described have resembled those caused by other MAO inhibitors Patients that developed hepatotoxicity are likely to have cross sensitivity with other MAO inhibitors Table 2. Features of TCP-induced hepatotoxicity. TCP: tranylcypromine; MAO: monoamine oxidase Case reports (only 1 case described with TCP!) Tranylcypromine (1964) To a 49-years old woman with involutional depression was tranylcypromine 20mg daily prescribed. 6 weeks after onset of treatment she complained of weaknesss and malaise. Subsequently, dosage tranylcypromine was increased to 30mg daily. One week later: nausea, diarrhea, and anorexia. Also, dark urine, light stools, jaundice, and epigastric pain relieved by vomiting. She had no history of alcohol abuse and she used no other medications. The liver was palpable 4 cm below the costal margin of the right side and was tender. The spleen was not palpable. There was no lymphadenopathy. Serological test for syphilis was negative. After 7 weeks first laboratory tests were performed as shown in table 3. The pathologist examined the liver biopsy taken and concluded that the observed changes were consistent with regressing viral hepatitis. In this case the clinicians and the patient agreed on giving a challenge dose: 24 hours after the first dose, liver enzymes elevated until 540 units and nausea and vomiting recurred. 2 months after tranylcypromine was stopped, liver function tests were normal and no liverrelated symptoms were present. Time After Starting Time After Stopping AST (U/L) Alk P (U/L) Bilirubin (mg/dL) Other Tranylcypromine taken for 7 weeks 670 26.5 14.9 410 5.0 340 3.2 36 6.5 0.9 Tranylcypromine restarted for 2 days 10 weeks (0) 21 days 19 0.6 Rechallenge 22 (0) days 540 1.1 23 (1) day 420 24 (2) days 200 0.5 25 (3) days 67 27 (4) days 31 0.4 Normal Values <35 <13 <1.2 Table 3. Liver enzymes indicating hepatocellular and cholestatic damage. AST: aspartate 7 weeks 8 weeks 9 weeks 10 weeks 0 5 days 10 days 17 days aminotransferase; Alk P: alkaline phosphatase Iproniazid/pheniprazine (1960) Patient: 52-year old woman with cardiac ischemic pain Medication: iproniazid Time interval: After 4 weeks Symptoms: malaise, dizziness, vomiting, and jaundice After 2 years, anticoagulant therapy was supplemented by pheniprazine 6 mg daily Time interval: After 7 months Symptoms: anorexia, malaise, jaundice, continuous upper abdominal pain, intense palmar erythema, liver edge was 3 cm below right costal margin and tender. Lab: bilirubin 12 mg/100ml, AP 36 units Decision: stop both ipronaizid and pheniprazine Patient died 2 months later due to a cardiac infarction. Pheniprazine/nialamide (1959) Patient: 60-year old woman with anxiety and loss of confidence Medication: pheniprazine 6 mg daily Time interval: After 3 months Symptoms: hematemesis After a few months pheniprazine was discontinued and restarted again because of depressive symptoms. Time interval: After 1 month Symptoms: malaise, anorexia, and jaundice. Liver 2 cm below costal margin. Lab: Bilirubin 3.3 mg/100 ml Biopsy: Patchy necrosis and infiltration of portal tracts by neutrophils, lymphocytes, and fibroblasts, and many contained fat-droplets. Gastroscopy: Single varix on the anterior wall of the oesophagus Decision: stop pheniprazine After 6 weeks, nialamide 25 mg was prescribed because of recurrence of depressive symptoms. Time interval: 3 weeks Symptoms: nausea, anorexia, jaundice, the liver was 3 cm below costal margin palpable. Decision: continuation of nialamide After 3 weeks the liver diminished in size, liver-function tests returned to normal and jaundice subsided. Pheniprazine (1960) Patient: 27-year old man with depression Medication: Pheniprazine 18 mg daily Time interval: after 2 months Symptoms: Upper abdominal discomfort, anorexia, and jaundice Decision: stop pheniprazine Jaundice progressively deepened, anorexia persisted. Lab: bilirubin 40 mg/100ml, AP 26 units Biopsy: necrosis of liver cells, with loss of lobular structure and invasion by inflammatory cells. Decision: prednisone was started A day thereafter, the patient collapsed and died. Phenelzine (1960) Patient: 56-year old woman Medication: phenelzine 30 mg daily Time interval: 5 months Symptoms: pruritis, pain behind the eyes, anorexia and jaundice Lab: Bilirubin 2.8 mg/100ml, AP 31 units Biopsy: patchy necrosis of parenchymal cells, with variation in nuclear size of the intact cells. The portal tracts and the necrotic areas were infiltrated by lymphocytes. Decision: Stop phenelzine 2 weeks later, the jaundice had subsided an liver function tests had returned to normal. 1. Bandt C, Hofbauer FW. Liver injury associated with tranylcypromine therapy. JAMA 1964 188: 752-3. 2. Holdswoth CD, Atkinson M, Goldie W. Hepatitis caused by the newer amine-oxidaseinhibiting drugs. Lancet 1961; 2: 621-23. 3. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 493-8. 4. Baker GB, Coutts RT, McKenna KF, et al. Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review. J Psychiatry Neurosci 1992;17:206-14 5. Prokai-Tatrai K, Pop E, Anderson W, et al. Redox derivatives of tranylcypromine: syntheses, properties, and monoamine oxidase inhibitor activity of some chemical delivery systems. J Pham Sci 1991;80:255-61 6. Fowler CJ, Mantle TJ, Tipton KF. The nature of the inhibition of rat liver monoamine oxidase types A and B by the acetylenic inhibitors clorgyline, I-deprenyl and pargyline. Biochem Pharmacol. 1982;31:3555-61 7. Li AP, Lu C, Brent JA, et al. Cyropreserved hyman hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, emtabolic stability, and drug-drug interaction potential. Chem Biol Interact. 1999;121:17-35 8. Yard and McKennis. Effect of structure of the ability of hydrazino compounds to produce fatty livers. J Pharmacol Exp Ther. 1955;114:391-7 9. https://livertox.nih.gov/Tranylcypromine.htm 10. https://pubchem.ncbi.nlm.nih.gov/compound/tranylcypromine#section=Substancesby-Category Questions: - Altitude of ALT/AST elevations: diagnostic discriminative? international expert group proposed following thresholds for diagnosis of DILI (drug-induced liver injury) (1): o ALT >5xULN (upper limit of normal) o ALP>2x ULN - Our casus has also elevated AP, GGT and LDH: what is the significance of this? o In book of prof Gouw: TCP causes combined cholestatic and hepatocellular injury.. In Zimmerman: only hepatocellular. - Maybe pre-existing NASH, with an exacerbation due to medication? - How long was our patient taking statins also known to increase liver enzymes.. 1. Kullak-Ublick GA, Andrade RJ, Merz M, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut 2017;66:1154-1164
