Lecture 5 and 6: Hepatic - Enzyme Induction & Inhibition (CYP450) - VOCAB Flashcards

Vocabulary-style flashcards covering hepatic metabolism, CYP450 isoenzymes, induction/inhibition mechanisms, drug interactions, and pharmacogenomics from the Case 3: Hepatic lecture notes.

Cytochrome P450 (CYP450)

A family of heme-containing enzymes in the liver that oxidize many drugs; Fe2+ coordinated with four porphyrin nitrogens; non‑porphyrin ligands include the sulfur of a cysteine, water, carbon monoxide, or oxygen; variations in the protein determine isoforms.

Isoenzyme

A variant form of an enzyme produced by different genes; >20 CYP isoenzymes identified in the human liver, grouped into four families denoted by CYP followed by numbers and letters (e.g., CYP2C9, CYP2D6).

Induction

Process by which exposure to a chemical increases production of a drug‑metabolizing enzyme, leading to higher metabolism of substrates and potential drug interactions (including autoinduction).

Inhibition

Process by which a chemical reduces enzyme activity, leading to higher drug levels and potential toxicity; mechanisms include competitive inhibition, enzyme destruction, or formation of inactive complexes.

Autoinduction

When a drug induces the enzymes that metabolize it, increasing its own metabolism over time.

CYP3A4

The major CYP isoenzyme in humans; metabolizes about 50% of drugs; inhibited by macrolides, azoles, and HIV protease inhibitors; induced by rifampin, glucocorticoids, St John’s wort, and other agents.

Inducers

Substances that increase CYP enzyme production; examples include carbamazepine, rifampin, phenobarbital, chronic ethanol, tobacco, St John’s wort, and glucocorticoids.

Inhibitors

Substances that decrease CYP activity; examples include cimetidine, erythromycin, ketoconazole, fluconazole, ritonavir, grapefruit juice (intestinal), and various HIV protease inhibitors.

Substrate

A drug that is metabolized by a particular CYP isozyme.

CYP2D6

Metabolizes >70 drug oxidations; shows genetic polymorphism with phenotypes from ultra‑rapid to poor metabolizers; inhibited by fluoxetine, amiodarone, and cimetidine.

Codeine metabolism

Codeine is a prodrug that is activated to morphine primarily by CYP2D6; ultra‑rapid metabolizers risk morphine toxicity; poor metabolizers have little analgesic effect.

CYP2D6 substrates

A broad range of drugs including codeine, tramadol, several antidepressants and antipsychotics; highly subject to genetic variation in activity.

CYP2C9 and warfarin

Warfarin is metabolized by CYP2C9; variants (e.g., *2, *3) reduce activity, increasing bleeding risk; CYP2C9 and VKORC1 polymorphisms influence warfarin dose.

VKORC1

Gene encoding vitamin K epoxide reductase; promoter polymorphisms (e.g., G3673A) affect warfarin dose requirements and sensitivity.

HLA polymorphisms and drug hypersensitivity

Polymorphisms in HLA-A and HLA-B loci associated with severe hypersensitivity reactions to certain drugs (e.g., carbamazepine).

DPYD

Gene encoding dihydropyrimidine dehydrogenase; deficiency increases toxicity risk with fluorouracil, capecitabine, and tegafur.

TPMT and NUDT15

Genes influencing azathioprine metabolism; variants affect toxicity risk and dosing.

Enterohepatic circulation

Conjugated drugs are excreted in bile to the gut, deconjugated by gut bacteria, and reabsorbed, prolonging drug effect (important for estrogens in the pill).

P‑glycoprotein (P‑gp, ABCB1)

An efflux transporter co‑expressed with many CYP substrates; interactions often involve both CYP enzymes and P‑gp, affecting absorption and disposition.

CYP1A2

Metabolizes caffeine and other substrates; inducible by various inducers (e.g., certain drugs and dietary components); activity varies among individuals.

CYP1A1

Binds and oxidizes planar aromatic substances; induced by polycyclic aromatic hydrocarbons (PAH); high levels in smokers; can activate aromatics to carcinogens; expression is variable.

CYP2B6

Metabolizes drugs such as mephenytoin, cyclophosphamide, some coumarins, and methadone; induced by rifampicin and phenobarbital.

CYP3A4 inhibitors and clinical impact

Inhibitors of CYP3A4 (e.g., macrolides, azoles, HIV protease inhibitors, grapefruit juice) can raise substrate drug levels and risk toxicity (e.g., statin rhabdomyolysis).

CYP3A4 inducers and clinical impact

Inducers (e.g., rifampin, rifabutin, phenobarbital, carbamazepine, St John’s wort) increase metabolism of substrates, possibly reducing efficacy or altering prodrug activation.

Induction mechanisms

Control of CYP transcription via ligand‑dependent nuclear receptors (e.g., PXR, CAR, GR); activated receptors increase transcription, producing more enzyme.

PXR and RXR

Nuclear receptors (pregnane X receptor and retinoid X receptor) that regulate expression of drug‑metabolizing enzymes and transporters in response to xenobiotics.

Nrf2 pathway

Keap1–Nrf2–ARE pathway; under stress, Nrf2 dissociates from Keap1, translocates to the nucleus, binds ARE, and induces detoxification and antioxidant genes.

Pharmacogenomics

Study of how genetic variation affects drug response; guides prescribing and decision‑making; includes pharmacokinetic and pharmacodynamic gene–drug interactions.

Clinically actionable gene–drug pairs

Gene–drug pairs with management implications (e.g., DPYD with fluorouracil; CYP2D6 with codeine; CYP2C19 with clopidogrel; CYP2C9 with warfarin; HLA alleles with carbamazepine).

Grapefruit juice interaction

Grapefruit juice inhibits intestinal CYP3A4, increasing plasma levels of substrates such as certain calcium channel blockers (e.g., felodipine).

Enterohepatic cycle and contraceptives

Liver conjugates estrogens; gut bacteria deconjugate allowing reabsorption; this enterohepatic circulation contributes to persistence of effect in oral contraceptives.

Pharmacokinetic vs pharmacodynamic interactions

Pharmacokinetic interactions alter drug concentrations (absorption, distribution, metabolism, excretion); pharmacodynamic interactions alter drug effects at targets or receptors.

Clinical examples of induction effects

Induction can lead to autoinduction or to altered metabolism of co‑administered drugs, changing efficacy or toxicity profiles.

CYP isoenzyme induction list (examples)

Inducers include carbamazepine, rifampin, phenobarbital, tobacco, chronic ethanol, St John’s wort; specific inducers per isozyme vary.

Clinical consequence: warfarin dosing

Variants in CYP2C9 and VKORC1 influence warfarin metabolism and sensitivity, requiring dose adjustments to avoid bleeding or thrombosis.

Clinical consequence: statin interactions

CYP3A4 inhibitors can raise levels of statins (notably simvastatin), increasing risk of rhabdomyolysis and toxicity.