Phase 1 reactions

Question 1

what is another word for phase 1 metabolism

Answer 1

functionalization

Question 2

what happens in phase 1

Answer 2

add or expose a functional group that can be converted to a water soluble conjugate

Question 3

what is the central component of the mixed function oxidase (MFO) system

Answer 3

cytochrome p450 enzyme

Question 4

where is cytochrome p50 foudn

Answer 4

bound to smooth endoplasmic reticulum membranes within a cell

Question 5

where is CYP450 most abundant

Answer 5

in the liver

Question 6

why is CYP450 essential

Answer 6

essential for metabolism of x and the production of essential molecules (cholesterol, steroids)

Question 7

what are the three mixed function oxidase system components

Answer 7

1. heme protein (cyp450)
2. dual flaboprotein (NADPH-P450 reductase_
3. phospholipids (phosphatidyl choline) in SER membrane provide support

Question 8

role of heme protein CYP450

Answer 8

binds substrate and catalyses metabolism

Question 9

describe the role of the dual flavoproteins (FAD, FMN)

Answer 9

• accepts 2e- from NADPH, passes 1e- at a time to CYP

- regenerates NADPH in the pentose phosphate pathway/hexose monophosphate shunt

Question 10

what are the cofactors needed in the MFO system

Answer 10

1. NADPH
   - source of reducing equivelents
2. O2
   - substrate accepts 1O, other O contributes to water

Question 11

what do CYP enzymes do

Answer 11

all CYP enzymes catalyze the mono oxygenation of one atom of oxygen into a substrate, and the other oxygen is reduced to water with reducing equivalents derived from NADPH

Question 12

what is at the centre of CYP

Answer 12

an iron-protoporphyrin (heme)

- FE3+ is an important site of action in phase 1 reactions

Question 13

what is the mechanism of action of CYP (7 steps)

Answer 13

1. X binds to ferric form of CYP= CYP-X complex
2. First e- reduction created ferrous CYP-X
   - NADPH donated 2e- to FAD of DADPH-P450 reductase
   - FAD passes e- to FMN
   - FMN passes 1e- to ferric CYP-X to create ferrous CYP-X
3. O2 binds to CYP-X
   - O2 binds fe2+ in close proximity to X
4. electron rearrangement
   - spontaneous transfer of e- from Fe2+ to O2 creates moderate, superoxide-like reactivity
5. second e- reduction
   - FMN passes second e- to CYP-X-O2 complex
   - creates extreme reactivity
6. reactive O attacks X
   - 1 O leaves as H2O
   - 1 O binds X = XOH
7. XOH is released as the reactive intermediate
   - CYP enzyme is recycled and ready to do it again

Question 14

what is the nomenclature of CYP

Answer 14

CYP followed by:

• Family number
• subfamily letter
• specific member number

Question 15

what are SNPs

Answer 15

inherited genetic variation when a single nucleotide is altered from wild type

Question 16

SNPs within genes encoding CYP enzymes can result in:

Answer 16

• increased CYP
• increased enzymatic activity
  produce phase 1 reactive intermediates faster

or

• decreased CYP
• decreased enzymatic activity
• produce phase 1 reactive intermediates slower