A phase I reaction introduces a functionally reactive polar group. If the metabolite formed is polar enough, it is readily excreted in the urine. If the metabolite is nonpolar, it undergoes a subsequent phase II reaction to form a more readily excretable polar conjugate. Phase I reactions occur mainly in the liver and are mostly catalyzed by the cytochrome P450 system of hemoproteins located in the lipophilic endoplasmic reticulum of the cells. In hepatic drug oxidation, the oxidized form of P450 first combines with the parent drug. The binary-drug complex formed is reduced by NADPH–P450 reductase. The reduced complex uses molecular oxygen and a second electron to form an "activated oxygen"-P450-substrate complex. The activated oxygen is then transferred to the drug to produce the oxidized drug metabolite. In short, in a phase I reaction a parent drug is oxidized to introduce a hydroxyl group via the monooxygenase P450 cycle.