Cytochrome P450

Cytochrome P450 (CYP450) is a large superfamily of heme-containing enzymes concentrated in the liver — though smaller amounts are present in the intestinal wall, lungs, and brain. Their primary role is Phase I drug metabolism: chemically modifying foreign compounds so the body can excrete them. The name comes from their spectroscopic signature, an absorption peak at 450 nanometres when carbon monoxide is bound to the enzyme.

There are dozens of human isoforms, each assigned a number, letter, and second number — CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2 being the five that account for the metabolism of the large majority of drugs in clinical use. Which isoform handles a given substance determines which other compounds can interfere with it, and how much genetic variation between individuals affects the response.

How it works · its role

Each isoform inserts a single oxygen atom into its substrate — typically forming a hydroxyl group — making the compound more water-soluble and ready for excretion or further processing. A metabolite produced this way may itself be pharmacologically active, sometimes more so than the parent compound; codeine, for example, is converted to morphine through this step.

Substances can act on CYP enzymes as inhibitors or inducers. An inhibitor reduces the activity of an isoform, causing co-administered substrates of that enzyme to accumulate in the bloodstream. An inducer upregulates enzyme production, accelerating clearance and blunting the effect of other substrates. These two mechanisms account for a large share of the drug-combination warnings on these pages.

Genetic polymorphisms add a further layer of variation. People with low-activity copies of CYP2D6 — called poor metabolisers — may reach toxic plasma levels at standard doses of a CYP2D6 substrate; ultra-rapid metabolisers may find the same dose ineffective.

Relevance to substances & effects

CYP2D6 metabolises MDMA, many opioids, and a wide range of antidepressants. When CYP2D6 is inhibited by one substance, the plasma level of any co-administered substrate of that enzyme rises in an unpredictable way. Several SSRIs are potent CYP2D6 inhibitors, which means they can alter the pharmacokinetics of many other substances taken alongside them.

CYP3A4, the most abundant hepatic isoform, handles benzodiazepines, many opioids, and a range of cannabinoids, among others. St. John's Wort is a well-characterised CYP3A4 inducer — regular use can measurably reduce the blood levels of other CYP3A4 substrates.

Beta-carboline alkaloids found in certain plant preparations — including the harmine and harmaline present in ayahuasca — inhibit CYP2D6, contributing to elevated and prolonged effects when combined with other substrates of that enzyme. Because the specific isoform involved determines which combinations carry risk, CYP450 involvement is a starting point rather than a complete picture; the interaction data for each substance records the relevant isoform where that information has been established.