Pathway 1/Phase 1 Reactions
Oxidation is probably the most common reaction in xenobiotic metabolism. This reaction is catalyzed by a group of membrane-bound monooxygenases found in the smooth ER of the liver and other extrahepatic tissues, termed the "cytochrome P450 monooxygenase enzyme system". Additionally, P450 has been called a mixed-function oxidase or microsomal hydroxylase. P450 functions as a multicomponent electron-transport system, responsible for the oxidative metabolism of a variety of endogenous substrates and exogenous substances, including drugs, carcinogens, insecticides, plant toxins, environmental pollutants, and other foreign chemicals.
Central to the functioning of this unique superfamily of heme proteins is an iron protoporphyrin. The iron protoporphyrin is coordinated to the sulfur of cysteine and has the ability to form a complex with carbon monoxide, resulting in a complex that has its primary absorption maximum at 450 nm. The most important function of P450 is to "activate" molecular oxygen (dioxygen), permitting the incorporation of one atom of oxygen into an organic substrate molecule concomitant with the reduction of the other atom of oxygen to water. The introduction of a hydroxyl group into the hydrophobic substrate molecule provides a site for subsequent conjugation with hydrophilic compounds (phase 2), thereby increasing the aqueous solubility of the product for transport and excretion from the organism. This enzyme system not only catalyzes xenobiotic transformations in ways that typically lead to detoxication but also, in some cases, in ways that lead to products having greater cytoxic, mutagenic, or carcinogenic properties.
Drug Conjugation Pathways (Phase 2)
Conjugation reactions represent probably the most important xenobiotic biotransformation reation. Xenobiotics are as a rule lipophilic, well absorbed from the blood, but excreted slowly in the urine. Only after conjugation (Phase 2) reactions have added an ionic hydrophilic moiety, such as glucuronic acid, sulfate ester, or glycine, to the xenobiotic is water solubility increased and lipid solubility decreased enough to make urinary eliminiation possible. The major proportion of the administered drug dose is excreted as conjugates into the urine and bile. Conjugation reactions can be preceded by Phase 1 reactions. For xenobiotics with a functional group available for conjugation, conjugation can be its fate.
The major conjugation reactions were traditionally thought to terminate pharmacologic activity by transforming the parent drug or Phase 1 metabolites into readily excreted ionic polar products. Moreover, these terminal metabolites would have no significant pharmacologic activity. This long-established view has changed with the discoveries that morphine 6-glucuronide has more analgesic activity than morphine in humans and that minoxidil sulfate is the active metabolite for the antihypertensive minoxidil. For most xenobiotics, conjugation is a detoxification mechanism. However, some compounds could form reactive intermediates that have been implicated in carcinogenesis, allergic reactions, and tissue damage.