| Localization of post enzymes involved in detoxification and drug excretion: | Hepatocyte (liver cell) smooth endoplasmic reticulum. |
| Phase I reactions: | These reactions are described as oxidation reductions and involve an oxygen-containing group added to the substance to be excreted. |
| Phase II reactions: | These reactions typically describe a covalent bond attachment of the drug to a water-soluble carrier molecule examples of which include glucuronic acid or glutathione. |
| Phase I reactions-drug inactivation or drug activation? | Both are possible. Most of the time reactions catalyzed by phase I enzymes inactivate the drug. Sometimes, however, and inactive drug (prodrug)
is metabolized to an inactive form. One example of this latter action is the anticancer drug cyclophosphamide which is activated to a cytotoxic electrophilic derivative. Another example is clofibrate, a prodrug which is converted from and inactive
ester form to an active acidic form |
| The main consequence of phase II reactions with respect to drug elimination: | The substrate (drug) for phase II reactions becomes more water-soluble as a result of the process.
Becoming more water-soluble enhances drug elimination from tissues often by means of efflux transporters. |
| Enzyme systems carrying out phase I reactions: | Phase I oxidative reactions are catalyzed by cytochrome P450 enzyme isoforms (CYP), flavin-containing monooxygenases (FMO), and epoxide hydrolases (EH). |
| Examples of phase II enzyme superfamilies: | Glutathione-S-transferases (GST), UDP-glucuronosyltransferases (UGT), sulfotransferases (SULT), and N-acetyltransferases (NAT) as well as methyltransferases (MT). |
| Relationship between phase I enzyme systems in phase II enzyme systems: | The phase I oxidative process may either add or expose a functional group. As a result, products of phase I reactions become substrates for phase II reactions (conjugating or synthetic). |
| Principal effect of glutathione-S-transferase (UGT) activity on drug elimination: | UGT activity involves the addition of glucuronic acid. The glucuronide metabolite, being more water-soluble, becomes more readily excreted in the urine or bile. |
| General localizations of drug metabolizing enzymes: | These enzyme systems, although found in most body tissues, are concentrated in the G.I. tract, including the liver, and small and large intestines. |
| Likely metabolic site for orally administered drugs: |
The liver is the major metabolic sites for endogenous substances such as cholesterol, proteins, fatty acids, steroid hormones as well as for drugs or more generally, xenobiotics.
A xenobiotic (pronounced "zenobiotic") is a chemical found in the body but not normally produced or anticipated to be there. Examples might include a drug, pesticide or carcinogen. |
| Pathway by which an orally administered drug reaches the liver: | The orally administered drug is absorbed by the small intestine and then transported to the liver through the portal vein. |
| Localization of drug metabolism sites in the G.I. tract: | This initial metabolic site is localized in GI epithelial cells. |
| Possible consequences of active drug reaching the liver through the portal vein pathway: | One possibility is that the drug, and sometimes
a substantial proportions of the drug is metabolized by the liver without the drug ever reaching the systemic circulation. This possibility is referred to as the first-pass effect. Some drug with limited first pass susceptibility reach the general circulation and is metabolized due to multiple passes through the liver (and possibly by other tissues). |
| Examples of non-hepatic (non-liver) site of drug metabolism: | Sites may include nasal mucosa and lung. These sites are of particular interest for metabolizing drugs administered by means of aerosol sprays. |
| Intracellular localization of xenobiotic-metabolizing enzymes: | These systems are localized in intracellular membranes and in the cytosol. The endoplasmic reticulum is a principal localization site for cytochrome P450 enzyme isoforms (CYPs), Flavin-containing monooxygenases (FMO), and epoxide hydrolases (EH). Some phase II conjugating enzymes including the UGTs (UDP-glucuronosyltransferases) are also localized in the endoplasmic reticulum. |
| Described the cytochrome P450 enzyme system: | CYPs represent an enzyme superfamily in which all members contain a heme molecule, noncovalently bound to the peptide chain. In the case of CYPs the heme, contains one iron atom in a hydrocarbon cage,
and binds oxygen at the active enzyme site. CYPs use oxygen along with hydrogen ion
(H+) derived from a cofactor, reduced nicotinamide adenine dinucleotide phosphate (NADPH) in the catalysis of substrate oxidation. The hydrogen ion comes from the activity of NADPH-cytochrome P450 oxidoreductase. In some cases substrate metabolism by a cytochrome P450 enzyme isoform results in the oxidized substrate and a water molecule as a byproduct. However, mainly the CYP-mediated reaction consumes more oxygen than substrate metabolized and produces an activated oxygen which is converted to water by another enzyme, superoxide dismutase. Higher levels of activated oxygen (a reactive oxygen species, ROS) may induce oxidative stress
that may damage cellular physiology and promote various pathologies. |
| Reactions catalyzed by mammalian CYP enzyme isoforms include: | N-oxidation, O-dealkylation, aromatic hydroxylation, S-oxidation, deamination, dehalogenation. |
| Non-drug metabolizing CYP enzyme isoforms: | CYPs that are involved in steroid and bile acid synthesis exhibit high substrate specificity. One CYP isoform, CYP19 a.k.a.aromatase only metabolizes testosterone or androstenedione while NOT metabolizing drugs or other xenobiotics. |
| An example of a specific aromatase inhibitor which may be used in treating estrogen-dependent tumors: | anastrozole |