WHAT IS DETOXIFICATION?

Detoxification is defined as biochemical processes whereby noxious

substances are rendered less harmful and more water soluble
Xenobiotic are compounds which may be accidentally ingested or taken as
drugs or compounds produced in the body by bacterial metabolism
Biotransformation is the process whereby a substance is changed from
one chemical to another by a chemical reaction within the body

PHASES OF DETOXIFICATION:
1. PHASE 1 REACTION:
a. ENZYME TRANSFORMATION:
- Either aromatic or aliphatic
- Performed by a family of enzymes called the cytochrome
P450s
- (CYPs)
- CYPs are able to recognize and modify countless different
toxins
- versatile
- However, they metabolize toxin very slowly
- CYP3A4 (1-20 molecules/sec) vs. SOD (million molecules/sec)
- Overcome by producing large amount of CYPs (5% of total
liver
proteins and intestines)
- Prominent role in the metabolism of prescription drugs (50%)
- Other enzymes in Phase 1: Flavin monooxygenase (FMOs),
alcohol
and aldehyde dehydrogenases, monoamine oxidases

2. PHASE 2 REACTION:
a. ENZYMATIC CONJUGATION:
- Why need phase II?
i. Phase I reactions are not sufficient to make the toxin water
soluble
enough to complete the entire excretion pathway
ii. Product from the phase I reactions have been rendered more
reactive than the original toxins
- Phase II
modify phase I products to both increase the
solubility
and reduce their toxicity
- Prominent role in the protection against chemical
carcinogenesis
especially at the initiation phase of cancers

Six important conjugation processes like glucuronidation,

glutathione
conjugation, sulphation, methylation, acetylation, amino acid
conjugation
Production of most phase II enzymes is controlled by a protein
called nuclear erythroid-derived 2 (Nrf2), a master regulator

of
antioxidant response
b. The role of NrF2:
- Nrf2 in cytoplasm, inactive oxidative stress activated
travel to nucleus turn on the genes of many antioxidant
proteins (glutathione & SOD)
- Important role in initiating heavy metal detoxification and the
recycling of CoQ10, a potent antioxidant
3. PHASE 3 REACTION:
a. Transport:
- Phase III transporters present in many tissues i.e. liver,
intestine, kidney and brain
- Provide a barrier against xenobiotic entry
- Necessary to excrete the newly formed phase 2 products out
of the cell
- Belong to a family of proteins called ABC Transporter (ATP
Binding
cassette)
- Require chemical energy (ATP) to actively pump toxins
through the cell membrane and out of the cell
- In liver: these transporters move glutathione, sulfate and
glucuronide conjugates out of cell into the bile for elimination

ENZYMES OF DETOXIFICATION:

PHASE 1 / 2 IMBALANCE:
OVERDOSE OF ANALGESIC ACETAMINOPHEN /
PARACETAMOL:
-

The most common cause of liver failure in US

Small amount : Phase 1 CYP enzymes transform it into toxic
metabolite
N-acetyl-p-benzoquinone imine (NAQPI) Phase 2 enzyme
GST conjugates glutathione
Normal therapeutic dose: Detoxified by the Phase 2 UGT and
SULT
enzymes
Overdose: UGT, SULT and GST enzyme will quickly be
depleted
NAQPI is produced faster than it can be detoxified NAQPI
accumulates in the liver widespread damage (lipid
peroxidation,
inactivation of cellular proteins, disruption of DNA metabolism)
Treatment: administration of the precursor amino acids for
glutathione synthesis (N-acetyl cysteine)

DETOXIFICATION SUPPORTS:
Bile secretion:
-

Functions as the major mechanism for moving conjugated

toxins out of the liver and into the intestines

Antioxidation:
-

Protects against the harsh phase 1 oxidation reaction which

frequently produce free-radical byproducts
Production of antioxidant enzymes is regulated by Nrf2

Heavy metal toxicity:

-

Could generate free radicals and deplete antioxidant reserves

Mercury, arsenic, lead: inactivate glutathione molecule
Lead: reduce activity of enzymes involved in recycling glut
Removal: Chelation by cellular proteins metallothioneins (MTs)
Production of MT is stimulated by Nrf2 with response to
cellular stress

IMPAIRED DETOXIFICATION:
-

Repeated exposure to chemicals and toxins in food, water and

the environment liver overload
Leaky gut: intestine allows large, undigested molecules to
pass into the body increased amounts of toxic substances
liver become overloaded
Slower detox results in more toxic substances circulating in
the body
Unchanged or partially changed toxins are not easily
eliminated and pass from the liver to the body
The toxins are stored in fatty body tissue, including the brain
and CNS cells
Stored toxin may be slowly released into the blood,
contributing to many chronic illnesses

SIGN OF STRESSED LIVER:

-

fatigue
headaches
chronic joint or muscle pain
digestion issues including gas, heartburn, bloating, diarrhea or
constipation, and abdominal pain
insomnia

autoimmune diseases
hormonal imbalances like PMS or menopausal symptoms
acne or skin rashes
anxiety or depression
allergies
inflammation
chemical sensitivities