Human liver microsomes

Human liver microsomes (HLM) are membrane fragments isolated from human liver tissue by high-speed centrifugation. When liver cells are disrupted and spun down, the smooth endoplasmic reticulum — the cellular compartment where most drug metabolism occurs — collapses into small sealed vesicles. These vesicles carry the enzyme machinery that transforms xenobiotics, including virtually every drug that enters the body.

In practice, HLM is prepared from tissue pooled across multiple donors to average out genetic variation between individuals. Adding a test compound and the appropriate cofactors to this preparation activates the resident enzymes under controlled conditions, generating metabolites that can be measured and identified.

How it works · its role

The enzymes most concentrated in liver microsomes belong to two main families: the cytochrome P450 (CYP) superfamily, which drives most oxidative phase I transformations, and the UDP-glucuronosyltransferases (UGTs), which couple compounds with glucuronic acid in phase II to make them water-soluble enough to excrete.

A standard HLM experiment adds the test compound together with NADPH — the cofactor CYP enzymes require — to the microsomal suspension. Researchers measure how quickly the compound disappears, what metabolites form, and which CYP isoforms are responsible, often by repeating the incubation with selective chemical inhibitors or with single-enzyme recombinant preparations.

The result is a kinetic profile: how fast an enzyme acts (Vmax), how tightly it binds the compound (Km), and an intrinsic clearance estimate that feeds predictions of hepatic extraction in a living person. This translation from dish to body carries real uncertainty and is one reason HLM data is treated as a starting point rather than a final answer.

Relevance to substances & effects

Nearly every psychoactive compound is eventually processed by the liver, and CYP enzymes — particularly CYP3A4, CYP2D6, CYP2C19, and CYP1A2 — handle the largest share. HLM studies establish which isoforms are involved, which matters because if two substances share the same metabolic route, one can slow the clearance of the other.

MDMA, for example, is both a CYP2D6 substrate and a potent inhibitor of that enzyme — a finding from microsomal work that helps explain why the drug's pharmacokinetics shift with repeated doses in the same session. Many opioids depend primarily on CYP3A4; most serotonergic psychedelics undergo significant hepatic oxidation.

SSRIs differ markedly in how strongly they inhibit individual CYP isoforms, which is why the interaction risk profile of fluoxetine differs from that of sertraline despite both belonging to the same drug class. These distinctions originate in microsomal data and flow into the combination warnings shown across the encyclopedia.

The key limitation: HLM describes what enzymes can do to a compound in a cell-free preparation, not what fraction of real-world elimination follows that route in a living person. Active transport proteins, gut-wall metabolism, plasma protein binding, and inter-individual variation in enzyme expression all shape the final outcome. Microsomal data is necessary but not sufficient for predicting whether a clinical interaction will be significant.