newborns have poor glucuronating ability due to a deficiency in UDP glucuronyl transferase, the enzyme that transfers activated UDPGA 

this leads to hyperbilirubinemia and gray baby syndrome (inability to conjugate chloramphenicol)

chloramphenicol

cats lack:

effect of genetic factors on phase 1 reactions

genetic factors effecting phase 2 reactions

there is genetic polymorphisms with which Cyp enzymes?

CYP2C9

CYP2C19

CYP2D6

CYP2A6

HOW TO REMEMBER: THEY ALL START WITH CYP2. THE FIRST TWO ARE C 9 &19.. SO REMEMBER 9. THE NEXT TWO ARE D6 AND A6 SO REMEMBER 6

which two animal species show no gender based differences in metabolism?

male rats vs female rats metabolism

enzyme inducers examples

induction leads to decrease in duration of action of drugs because the enzymes are metabolizing faster. 

phenobarbital

carbamazepine

polycyclic aromatic hydrocarbons (PAH)

polychlorinated biphenyls (pcb)

environmental contaminents

cigarette smoke

dietary substances 

enzyme inhibitors

increase duratoin of action of drugs and lead to side effects bc of drug accumulation

some drugs and xenobiotics

grapefruit

substrate compitition 

inactivation of drug metabolizing enzymes

phenylbutazone inhibits metabolism of warfarin

dicoumerol, chloramphenical, phenylbutazone inhibit metabolism of tolbutamide leading to hyperglycemia. 

N-dealkylation

substrate: secondary and tertiary amines

mechanism: alkyl group attached to N is removed, making secondary amine primary, and tertiary amine secondary. 

byproduct: CH2O (corresponding aldehyde, which includes the O inserted by CYP450)

example: Methamphetamine (secondary amine) -> Amphetamine (primary amine)... think of it as the same molecule with the "meth" for methyl group removed.

substrate: secondary and tertiary amines

mechanism: alkyl group attached to N is removed, making secondary amine primary, and tertiary amine secondary. 

byproduct: CH2O (corresponding aldehyde, which includes the O inserted by CYP450)

example: Methamphetamine (secondary amine) -> Amphetamine (primary amine)... think of it as the same molecule with the "meth" for methyl group removed.

it usually happnes in the smallest alkyl group. (removal of it)

tertiary amines go through the reaction faster than secondary because of lipid solubility. 

this is because primary and secondary more polar molecules don't pass the membrane and reach the receptor as easily. 

substrate: primary and secondary amines where Alpha carbon can undergo hydroxylation

mechanism: CYP450 inserts O between C &H atom, unstable carbonylamide intermediate

Prodcts: corresponding ketone and amino group

example: amphetamine -> phenylacetone + ammonium

alpha carbon of amphetamine loses its amino group and it is replaced with a C=O

substrate: primary and secondary amines where Alpha carbon can undergo hydroxylation

mechanism: CYP450 inserts O between C &H atom, unstable carbonylamide intermediate

Prodcts: corresponding ketone and amino group

example: amphetamine -> phenylacetone + ammonium

alpha carbon of amphetamine loses its amino group and it is replaced with a C=O

-Replacement of an H with an insertion of O

phase 1 hydroxylation reactions:

oxidative deamination (alpha carbon's H is replaced with a carbonyl bond, and the amine group cleaves off)

N-Hydroxylation:(in amine molecules without alha carbon. O is inserted between N&H, so H becomes OH.)

Hydroxylation of aromatic systems: (O inserted making an epoxide out of a double bond, which undergoes rearrangement... ultimately replaces H with -OH. 

substrate: primary and secondary amines that dont have an alpha carbon with a free H. (therefore can't undergo N dealkylation)

mechanism: O is inserted between N and H. H becomes OH group.

substrate: primary and secondary amines that dont have an alpha carbon with a free H. (therefore can't undergo N dealkylation)

mechanism: O is inserted between N and H. H becomes OH group.

starts off as secondary amine, oxidized twice. 

1. oxidative N-dealkylation removes the methyl group on N producing Amphetamine, a primary amine. this metabolite is still active

2.Oxidative Deamination (insertion of =O on alpha carbon,    amine group leaves to produce inactive metabolite phenyl acetone (and ammonium as byproduct)

O-dealkylation

ex: phenacetin to acetaminophen

substrate: ether (C-O-R)

Product: product: alcohol and corresponding aldehyde

mechanism: OH is added to the alpha carbon, the entire alkyl (R) group cleaves off and has a newly =O attached.

ex: phenacetin to acetaminophen

substrate: ether (C-O-R)

Product: product: alcohol and corresponding aldehyde

mechanism: OH is added to the alpha carbon, the entire alkyl (R) group cleaves off and has a newly =O attached.

similar to O & N dealkylation. 

since few drugs contain S-alkyl groups, this reaction is uncommon

oxidation of thioesters (R-S-R) (aromatic and aliphatic)

substrate: R-S-R (sulfide/thioether)

oxidated twice. 

first into a sulfoxide (=O attached to S)

then into a Sulfone (two =O groups attached to S)

substrate: Thiocarbonyls (S=C) and thiophosphates (S=P)

mechanism: O is added between S=P, opening the bond up into what looks like S-P-O epoxide intermediate. 

the intermediate is unstable and it collapses, losing S and generating a double bond between P and O. 

S=P -> O=P

Parathione -> Paraoxon

substrate: Thiocarbonyls (S=C) and thiophosphates (S=P)

mechanism: O is added between S=P, opening the bond up into what looks like S-P-O epoxide intermediate. 

the intermediate is unstable and it collapses, losing S and generating a double bond between P and O. 

S=P -> O=P

Parathione -> Paraoxon

substrate: primary and secondary amines with no free H on alpha carbon

product: N-Hydroxyl intermediate

N-H --> N-OH

substrate: aromatic system

produces arene oxide intermediate which is very unstable. 

mechanism: O is added between 2 C's on the ring, and an epoxide is formed. spontaneous rearrangement via NIH shift results in an arenole: the aromatic compound with -OH group attached

1. spontaneous rearrangement & NIH shift resulting in arenol. this is most common pathway

2.glutathione conjugation to produce glutathione adduct

3. the epoxide (highly electrophilic) attaches to nucleophiles in the body's macromolecular adduct .. like DNA , RNA and protein.  this is what we dont want to happen
 

4. arene oxide + H2O --> trans di hydrodiol --(DHD Dehydrogenase)--> catechol metabolite

• addition of water opens up the epoxide so that ther are 2 OH groups.. DHD dehydrogenase makes the ring aromatic again  

1. nitro to amino

2. azo to amino

3. aldehydes/ketones to alcohol

Substrate: Aromatic Nitro compounds

• nitro group: N=O O (negative oxygen positive nitrogen)

2 intermediates:

1.nitroso (Ar-N=O)  

2. hydroxylamine ( Ar-NHOH)

final product: amine (Ar-NH2)

each step = 1 reduction.  you go from =O, to -OH, to H (attached to amine & aromatic compound)

substrate : Ar-N=N-Ar'

hydrazo intermediate: Ar-Nh-NH-Ar'

products: 2 primare amine metabolites: Ar-NH2 + H2N-Ar'

enzyme: azo reductases and bacterial reductase

product: alcohol & acid 

example: asprin