Phase 1 Reactions

Oxidation

• same enzyme can catalize different substances

• for a given substances there can be a sequence of multiple reactions, with intermediate metabolites in Phase 1

• multiple enzymes may act on the same compound

toulene phase 1 reactions

• From methylbenzene (toluene) to benzenecarboxylic acid

(Benzoic acid):

-The P450 enzyme CYP2E1 is the most active in oxidizing toluene

to forming benzyl alcohol. Other P450 enzymes, CYP2B6,

CYP2C8, CYP1A2, and CYP1A1, also contribute to the benzyl

alcohol formation.

- From alcohol to aldehyde and then to carboxylic acid, by ADH

and ALDH enzymes

Benzene

It is not metabolized into toulene but metabolized in the liver into hydroxylated and ring opened products some of which are toxic

oxidation of para position on benzene

Phenobarbital

Reductive Reactions

Carbonyl, nitro, and azo groups can be

reduced by reductases.

1. Carbonyl groups (C=O)  alcohols

2. Nitro ( -NO2) is reduced to amino

derivatives.

3. Azo groups (-N=N-) is reduced to amino

derivatives.

• hydroxul and amino functional groips can go onto Phase II

Reduction of Levonorgestreal

Phase I reductive biotransformation of the oral contraceptive
levonorgestrel – the morning-after pill. A Form of progestin used to stop
or delay ovulation and thickens the cervical mucus. It may prevent
implantation.

Nitrobenzene

• The most common exposure is at workplaces that use nitrobenzene to

produce dyes, drugs, pesticides or some types of rubber. Exposure can

occur through the air you breathe or through touch.

• Exposure pathways:

1. Breathing it in air at work, or near factory sites where nitrobenzene is used or

made, or near hazardous waste sites.

2. Drinking water with nitrobenzene in it. This can occur near hazardous waste sites.

3. Touching materials made with nitrobenzene.

4. Eye Contact by splashing the chemical in your eyes if you work where nitrobenzene

is used

• Toxicity, all routes: It can cause skin and eye irritation, decrease blood's

ability to carry oxygen (methemoglobinemia), cause liver injury and

reproductive toxicity. It is possible carcinogenic in humans.

Aspirin Hydrolysis

Aspirin (acetylsalicylic acid) is hydrolyzed into salicylic acid in the

stomach, in the intestinal mucosa, in the blood and mainly in the liver.

• Salicylic acid is the active metabolite responsible for most anti-

inflammatory and analgesic effects.

• Acetylsalicylic acid, the parent compound, is active for the antiplatelet-

aggregating effect. Acetylsalicylic acid may also have anti-inflammatory

effects.

Unmasking

P450 Enzyme System

• The human body has 57 genes encoding cytochrome P450 (CYP)

enzymes, which are a group of enzymes primarily involved in drug

and xenobiotic metabolism, with some also playing roles in

endogenous processes.

• Majority of P450 enzymes catalyze oxidation reactions, others also

catalyze reductions, rearrangements and other non-redox reactions.

CYP450 in Oxidative Reaction (1)

are the most common. These enzymes are hemoproteins (i.e. they contain
heme and iron) and involve molecular oxygen (O2). CYP450 enzymes belong to a class of enzymes known as monooxygenases, also called mixed function oxidases.

CYP45- in Oxidative Reactions (2)

• Accessible carbons are readily oxidized. For

instance,

1. Unhindered methyl substituents are often oxidized

to form alcohols, which can undergo further

oxidation to the carboxylic acid.

2. Other carbons such as carbon atoms in the alpha

position to a heteroatom (any atom that is not

carbon or hydrogen) can also undergo oxidation

(alpha oxidation).

3. On a benzene group, para position is often favored.

• Note:

• Epoxygenaseses derive The three-membered ring

epoxide from alkenes.

• Epoxides are hydrolyzed by soluble epoxide

hydrolase (sEH) in the liver into corresponding

diols.

CYP450 in Oxidative Reaction (3)

Hexachlorobenzene was used as a fungicide in the

United States from 1960s to 1984.

• Oxidative degradation Intermediates,

hexachlorobenzene epoxide and 1,4-

tetrachloroquinone can rapidly arylate cellular

macromolecules

• Benzoquinones may generate reactive oxygen

species.

• Tetrachloro-p-benzoquinone (TCBQ) is one of the

most electrophilic quinones because the four

chlorine substituents strongly withdraw electron

density from the quinone ring.

Adducts to CYP3A4

TCBQ forms covalent adducts with accessible cysteine residues in

CYP3A4

• Structural disruption

• Loss of catalytic activity

• Note: This typically does not involve direct binding to Cys442 at the

active center, but rather other accessible cysteines.

Oxidative demethylation of caffeine

• Oxidative N-demethylation reaction catalyzed by cytochrome P450

(CYP) enzymes

• Caffeine is a more potent central nervous system (CNS) stimulant,

while theophylline is more specialized for relaxing bronchial muscles

(treating asthma)

CYP450 in reductive reactions

• Under certain conditions, particularly anaerobic conditions, many cytochrome P450s can

function as a reductases. The most well-recognized reaction in this regard is probably

reductive dehalogenation.

• Cytochrome P450 could catalyze the reductive removal of halogens from

polyhalogenated alkanes such as hexachloroethane (188), to yield the corresponding

carbon-based radical. The radical would then undergo a second one-electron addition,

to yield the carbanion. Elimination of a chloride ion or the addition of a proton yielded

the observed products, tetrachloroethylene (189) and pentachloroethane (190),

respectively.