1 metabolism

Question 1

what is the definition of biotransformation?

Answer 1

the enzyme-catalyzed conversion of one xenobiotic into another
-the most important determinant of the duration of action of xenobiotics in the body

Question 2

what is detoxification?

Answer 2

-biotransformation results in a less toxic metabolite
-most common one that happens

Question 3

what is bioactivation?

Answer 3

-biotransformation results in a more toxic metabolite

Question 4

what is biotransformation in a nutshell?

Answer 4

the lipophilic nature of xenobiotics is also a hindrance to their elimination from the body
-thus the biotransformation (or metabolism) of xenobiotics to more water-soluble metabolites is essential to terminate their biological activity and eliminate them from the body
-biotransformation enzymes convert lipophilic xenobiotics into high water-soluble metabolites that are easily excreted from the body (mainly in urine and to a lesser extent bile/feces)

Question 5

biotransformation reactions are categorizes as either _________ or _________ reactions

Answer 5

phase 1 or phase 2
-as the terms suggest, a xenobiotic is often biotransformed sequentially through both phase 1 and phase 2 reactions

Question 6

what is phase 1 of biotransformation reactions?

Answer 6

-biotransformation enzymes modify the xenobiotic molecule mainly by oxidation (ex: addition of an OH (hydroxyl) group to the xenobiotic)

Question 7

what is phase 2 of biotransformation reactions?

Answer 7

-synthetic reactions that conjugate the xenobiotic with a highly polar endogenous compound in the cell (ex: a carbohydrate, sulphate, or acetate)

Question 8

the _________________ is the most important site of xenobiotic biotransformation

Answer 8

LIVER

Question 9

what are the important biotransformation reactions we will focus on?

Answer 9

Question 10

what is important in phase 1 reactions?

Answer 10

cytochrome P450-dependent monooxygenases (CYPs: aka mixed function oxidases) are the major phase 1 oxidative enzymes

Question 11

what do cytochrome P450 enzymes do? and where are they found?

Answer 11

-reactions usually involve adding or exposing a polar functional group (OH, COOH, NH2) to lipophilic xenobiotic molecule
-CYP enzymes that biotransform xenobiotics are located on smooth endoplasmic reticulum

Question 12

are CYPs only involved in biotransformation of xenobiotics?

Answer 12

-not only involved in biotrans of xenos but also a wide variety of catabolic (degradation) and anabolic (synthesis) reactions involving endogenous compounds (Ex; steroid hormones)

Question 13

how many different kinds of CYP enzymes are there?

Answer 13

> 100 different CYP enzymes have been identified (designated in families such as CYP1< CYP2, CYP3, subfamilies CYP1A, CYP2E, CYP3A and specific enzymes CYP1A2, CYP2E1, CYP3A4, based on DNA sequence similarity of genes coding for enzymes

Question 14

what does broad and overlapping mean?

Answer 14

very “versatile” and unique enzymes due to broad and overlapping substrate specificities (CYP)
-broad: one enzyme can biotransform many xenobiotics
-overlapping: one xenobiotic can be biotransformed by several enzymes

Question 15

what do CYP enzymes usually do?

Answer 15

CYP enzymes usually inactivate (detoxify) a xenobiotic but in certain cases can bioactivate a xenobiotic to a more pharmacologically or toxicologically active metabolite

Question 16

what are two examples of a biotransformation from a metabolite to one with much larger activity?

Answer 16

Question 17

graph of where CYP enzymes are found?

Answer 17

Question 18

what is the graph of a basic hydroxylation reaction?

Answer 18

Question 19

why is cholesterol important?

Answer 19

many enzymes involved in steroidogenesis are CYPs

Question 20

what are all the phase 1 oxidation reactions?

Answer 20

Question 21

what happened when vertebrate animals evolved a GI tract?

Answer 21

when vertebrate animals evolved a GI tract, this became a major route of exposure toxic substances (ex: plant toxins)
-to survive, animals had to evolve a strategy to intercept and detoxify potentially lethal substances

Question 22

what was solution to the GI tract problem?

Answer 22

-accomplished by the hepatic portal venous system, which delivers all substances absorbed from the GI tract to the liver (with its extensive biotransformation capacity) before they reach the systemic circulation and be delivered to the rest of the body (to exert effects)

Question 23

what is the first-pass effect?

Answer 23

the first-pass effect can result in nearly complete inactivation (>90%) of certain drugs (and xenobiotics) after oral ingestion
-for this reason, certain drugs are not given orally and are administered via different routes (ex: nitroglycerin given sublingually)

Question 24

what is oral bioavailability?

Answer 24

-the fraction of an orally administered drug that reaches the systemic circulation in an unchanged form
Bioavailability= AUCoral/AUCiv
AUC=area under the curve