smooth endoplasmic reticulum

STRUCTURE: Continuous with the rough ER (RER) but lacks ribosomes, so it appears as anastomosing tubules rather than flattened cisternae. Does not stain basophilic (unlike RER, which is basophilic due to ribosomal RNA).

FUNCTIONS: 1) Steroid hormone synthesis: Cholesterol-derived hormones (cortisol, aldosterone, androgens, estrogens, progesterone) are made in SER-rich cells of the adrenal cortex, testicular Leydig cells, and ovarian cells. Early steps occur in mitochondria (cholesterol to pregnenolone via desmolase, the rate-limiting step), with later steps in SER. 2) Detoxification (Phase I metabolism): Hepatocyte SER contains the cytochrome P450 monooxygenase system (oxidation, reduction, hydrolysis) that makes xenobiotics more polar. Chronic exposure to inducers (phenobarbital, rifampin, carbamazepine, phenytoin, chronic alcohol, griseofulvin, St. John's wort) causes SER hyperplasia and enzyme induction, which leads to faster drug clearance. Inhibitors (cimetidine, ketoconazole, ciprofloxacin, grapefruit juice, macrolides except azithromycin, amiodarone) have the opposite effect. 3) Lipid and phospholipid synthesis: Makes membrane phospholipids, triglycerides, and cholesterol; lipoprotein assembly in the liver and enterocytes. 4) Carbohydrate metabolism: Glucose-6-phosphatase is located in the SER membrane of hepatocytes, which allows release of free glucose in gluconeogenesis and glycogenolysis. Deficiency causes von Gierke disease (GSD type I): severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia. 5) Calcium storage and release: In muscle the specialized SER is the sarcoplasmic reticulum, which releases Ca2+ via the ryanodine receptor (RyR1) after dihydropyridine receptor activation and reuptake via SERCA. Malignant hyperthermia (RYR1 mutation, triggered by volatile anesthetics and succinylcholine) is treated with dantrolene. Brody disease involves SERCA1 mutation. 6) Glucuronidation (Phase II): UDP-glucuronosyltransferase is in the SER. Relevant in bilirubin conjugation (deficiency causes Crigler-Najjar and Gilbert syndromes) and in neonatal physiologic jaundice.

CLINICAL PEARLS: - Cells with extensive SER: hepatocytes, steroid-producing cells, and muscle cells. - RER vs. SER: RER is found in cells that make secretory proteins (plasma cells, pancreatic acinar cells, goblet cells, fibroblasts) and in neurons (Nissl bodies). It handles N-linked glycosylation and protein synthesis for secretion or membranes. SER does not synthesize proteins. - Free radical injury and toxins (e.g., CCl4) cause ER swelling and detachment of ribosomes, which are early reversible changes in cell injury. - Acetaminophen is metabolized by CYP2E1 to the toxic metabolite NAPQI, which is detoxified by glutathione. Overdose depletes glutathione and causes centrilobular (zone 3) necrosis, since zone 3 has the highest P450 activity. Treat with N-acetylcysteine. - Ethanol induces CYP2E1 (via the microsomal ethanol oxidizing system, MEOS) in chronic use.