Constitutive vs. Inducible Enzymes

Definitions

Key Characteristics

• Carry out essential "housekeeping" metabolic functions that must occur at all times (e.g., glycolysis, lysosomal digestion)
• COX-1 is the classic example - it constitutively produces prostaglandins for gastric cytoprotection, platelet aggregation, and vascular homeostasis, even in platelets that lack nuclei and cannot produce an inducible enzyme on demand (as noted in Firestein & Kelley's Textbook of Rheumatology)
• eNOS (endothelial NOS) is constitutive, producing low, steady levels of NO for physiologic vascular tone regulation (Basic Medical Biochemistry - A Clinical Approach, 6e)
• Defects in constitutive enzymes cause disease even without any environmental trigger (e.g., glucocerebrosidase deficiency in Gaucher disease)

• Expressed only when the cell encounters a specific signal - substrate, hormone, or inflammatory mediator
• Glucokinase (liver) is induced by insulin in the fed state; its concentration rises with high blood glucose and falls during fasting (Basic Medical Biochemistry - A Clinical Approach, 6e)
• COX-2 is induced by inflammatory cytokines and mediates pain, fever, and inflammation - this is why selective COX-2 inhibitors (e.g., celecoxib) are anti-inflammatory while sparing the gastric mucosa
• iNOS is induced by pro-inflammatory cytokines (e.g., LPS, TNF-α), producing large amounts of NO that drive vasodilation and hypotension in sepsis
• PEPCK and Glucose-6-phosphatase are induced during fasting (by glucagon, glucocorticoids) to upregulate gluconeogenesis

Classic Example: The lac Operon (Microbiology)

• In the absence of lactose, a repressor protein blocks transcription of beta-galactosidase, permease, and transacetylase
• When lactose is present, an inducer molecule (allolactose) binds the repressor, releasing it from the operator and allowing transcription to proceed
• This is the prototype for substrate-induced enzyme synthesis

Clinical Relevance

Acetaminophen (Paracetamol / APAP)

1. Basic Profile

• Class: Non-opioid analgesic and antipyretic (not an NSAID - lacks significant anti-inflammatory activity)
• Other names: Paracetamol (international), Tylenol, Panadol
• Active metabolite of phenacetin (phenacetin was withdrawn due to nephrotoxicity; acetaminophen retains the analgesic effect without causing interstitial nephritis or papillary necrosis)

2. Mechanism of Action

• Central COX inhibition: Acetaminophen inhibits prostaglandin E2 (PGE2) synthesis in the CNS, either via direct COX-2 inhibition or inhibition of membrane-associated prostaglandin synthase. It is a weak COX-1 and COX-2 inhibitor in peripheral tissues - this is why it has no significant anti-inflammatory effect peripherally (Katzung's Basic and Clinical Pharmacology)
• COX-3 variant: It has been proposed to inhibit a COX-1 variant (sometimes called COX-3), especially for thermoregulation (ROSEN's Emergency Medicine)
• Endocannabinoid/serotonergic pathway: The metabolite AM404 (formed in the CNS) activates cannabinoid CB1 receptors and TRPV1 vanilloid receptors, contributing to analgesia. Interactions with the serotonergic system are also described (Morgan & Mikhail's Clinical Anesthesiology)

3. Pharmacokinetics

4. Metabolism - The Critical Concept

1. Glucuronidation (40-67%) - by UDP-glucuronosyltransferase → nontoxic APAP glucuronide → excreted in urine
2. Sulfation (20-46%) - by phenosulfotransferase → nontoxic APAP sulfate → excreted in urine
3. CYP oxidation (5-15%) - primarily by CYP2E1 (also CYP1A2 and CYP3A4) → NAPQI (N-acetyl-p-benzoquinone imine), a highly reactive, cytotoxic electrophile
   • In therapeutic doses, NAPQI is rapidly detoxified by conjugation with glutathione (GSH) to form nontoxic mercaptate and cysteine conjugates → excreted in urine

5. Indications

• Mild to moderate pain (headache, myalgia, osteoarthritis, postoperative pain)
• Fever (antipyresis)
• Preferred over aspirin in: patients with hemophilia, peptic ulcer disease, aspirin-sensitive asthma/bronchospasm, children with viral illness (avoids Reye syndrome risk)
• Often combined with opioids for moderate-severe pain (opioid-sparing effect)
• Safe in pregnancy (though recent data suggest possible concerns with prolonged use)

6. Dosing

7. Toxicity - Hepatotoxicity (Most Important Adverse Effect)

Toxic Doses

• Minimum hepatotoxic single dose: 7.5-10 g (adults); 150 mg/kg (children)
• Severe hepatotoxicity: typically requires >15-25 g
• Chronic alcoholics: as little as 2-6 g/day can be fatal

Mechanism of Hepatotoxicity

• NAPQI accumulates → depletes GSH → covalently binds to hepatocyte proteins → centrilobular (zone 3) necrosis (because CYP2E1 is concentrated in zone 3)
• With severe toxicity: necrosis extends to submassive/panacinar pattern

Risk Factors for Hepatotoxicity (Sleisenger & Fordtran's)

Clinical Stages of Overdose

8. Rumack-Matthew Nomogram

• Level above the treatment line → NAC indicated
• Not applicable for chronic/repeated ingestions

9. Antidote: N-Acetylcysteine (NAC)

1. NAC¹ - Enhances sulfation (diverts APAP away from toxic pathway)
2. NAC² - Serves as glutathione precursor (replenishes GSH stores)
3. NAC³ - Acts as a direct glutathione substitute, binding NAPQI directly
4. NAC⁴ - Free-radical scavenger; improves hepatic microcirculation and oxygen delivery even after hepatotoxicity is established

NAC Dosing Regimens

• 150 mg/kg over 15 min in 200 mL D5W
• Then 50 mg/kg over 4 hours
• Then 100 mg/kg over 16 hours (total ~300 mg/kg over 24 hours)

Timing of NAC

Key rule: For maximum benefit, NAC must not be delayed beyond 8 hours after ingestion (ROSEN's Emergency Medicine). If >8 hours have passed, initiate NAC immediately without waiting for labs.

10. Other Adverse Effects

• Renal: Acute tubular necrosis (with or without liver injury); mediated by renal CYP enzymes
• Rare: Hemolytic anemia, methemoglobinemia, anaphylaxis, serious skin reactions (Stevens-Johnson, DRESS) - very rare
• Hepatic enzyme elevation: Mild reversible rise in LFTs even at therapeutic doses
• No platelet effects, no GI ulceration, no uric acid effects

11. Contraindications / Cautions

• Active liver disease or cirrhosis (reduce dose, use with caution)
• Significant alcohol use disorder (lower threshold for toxicity)
• Malnutrition / prolonged fasting (depleted GSH)
• Concurrent use of enzyme-inducing drugs (isoniazid, phenytoin, carbamazepine, rifampicin)
• G6PD deficiency (risk of hemolysis with large doses)