Xenobiotic Metabolism PDF

3 PHASES OF
XENOBIOTIC
METABOLISM
INTRODUCTION TO XENOBIOTICS
*Recall: Foreign chemicals are

synthesized within the body are
termed xenobiotics (Gr.Xenos
meaning “strange”)*
• Xenobiotics may be naturally

occurring chemicals produced by
plants, microorganisms, or animals
(including humans).
• Xenobiotics may also be synthetic chemicals produced by humans.
Poisons are xenobiotics, but not all xenobiotics are poisonous.

How Does the Body Prevent the
Actions of Xenobiotics ?
1) Redistribution
2) Excretion – (primarily water soluble compounds)
- kidney and liver
3) Metabolism – the major mechanism for terminating
xenobiotic activity, and is frequently the single most
important determinant of the duration and intensity
of toxic responses to a xenobiotic.
- LIVER, kidney, lung, GI, and others
Note: 1) and 2) are highly dependent upon 3)
Xenobiotics at Work
TOXICOKINETICS
Xenobiotic
Excretion
DETECTION OF TOXIC BURDEN
• Ammonia burden
• Citrate, isocitrate, cis-aconitate
• Orotate
• 8-OH-dG
• p-hydroxyphenyllactate
• 2-Methylhippurate
• Dysbiosis markers
ADDITIONAL MARKERS OF
TOXICANT EXPOSURE
• Urinary glucarate
• Phase I and II upregulation
• herbicide, fungicide, petrochemical, alcohol and drug exposure
• Urinary benzoate
• Glycine conjugation
DETECTION OF TOXIC BURDEN
• Porphyrins
• Heavy Metals
• Whole blood, RBC, serum
• Urine
• Hair
HOW XENOBIOTICS CAUSE TOXICITY
Some xenobiotics cause toxicity by disrupting normal cell functions:
• Bind and damage proteins (structural,

enzymes)
• Bind and damage DNA (mutations)
• Bind and damage lipids
• React in the cell with oxygen to form

“free radicals” which damage lipid, protein,
and DNA
PHASES OF DETOXIFICATION
• Phase I:
• primarily cytochromes
• addition of functional groups
• Phase II:
• conjugation reactions
• attaches a water-soluble moiety
• Phase III:
• antiporter system
Phase I Nutrients: Antioxidants: Phase II Nutrients:
B vitamins Phytonutrients Glycine
Glutathione Vitamin C, E NAC
Flavanoids Minerals B vitamins
Phase I Phase II
Toxins (Cytochrome P450) Intermediate (Conjugation Pathways)
Excretion:
Reactions: Oxidation Metabolite Sulfation
Blood
Amino Acid conjugation
Urine
Glucronidation
Feces
Glutathione
Metnhylation
Free ROS
Radicals
Cell damage
PHASE I
• Operates via Cytochrome P450 enzymes (Cyp)
• Bioactivation – adds an attachment site to the toxin - Requires

NADH (from niacin)
• Can result in a more toxic toxin
• Generates reactive oxygen species – thus ensuring antioxidant

status is important
Phase I metabolism - CYP Introduction to Pharmacology Octobe 4, 2007
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PHASE I - CYP LIVER ENZYMES
P450 Enzyme Percent of Substrates

Total
Cyp3A4,5 29% Testosterone, cyclosporine
Cyp2C8,9,18 18% Warfarine, R-mephenytoin
Cyp1A2 13% Cafeine, aflatoxin B1
Cyp2E1 6% Ethanol,
Carbon tetrachloride
Cyp2A6 4% Coumarin
PHASE II
• Products of phase I detoxification are further metabolized

• Water soluble molecules are added creating inactive
products called conjugates that are excreted in bile and
urine
• Conjugases
• Sulfation
• Glucuronidation
• Amino acid conjugation
• glycination
• Glutathione conjugation
• Methylation
• Acetylation
GLUTATHIONE AND SULFATE CONJUGATE
FORMATION
PHASE I AND II ENZYME INDUCTION
• Mono-functional inducers
These elevate Phase II enzymes (such as glutathione S-transferases, NAD(P)H:quinone reductase,
UDP-glucuronosyl-transferases) in various tissues without significantly raising the Phase I
enzyme
Examples: cigarettes, charred meats, glucocorticoids,
• Bi-functional inducers
These induce both Phase I and Phase II enzymes
of xenobiotic metabolism.
Examples: flavonoids, garlic, rosemary, soy, cabbage, polycyclic
aromatic hydrocarbons
USE OF CHALLENGE COMPOUNDS TO
EVALUATE PHASES OF
DETOXIFICATION
CAFFEINE CLEARANCE
• 200 mg dose
• 2 and 8 hour saliva collection
• Phase I microsomal P450 mixed function oxidase activity
CAFFEINE CLEARANCE
If High:
• Liver is actively removing caffeine
• Enzyme induction
• Minimize exposure to environmental toxins
If Low:
• Genetic polymorphisms or loss of liver function
• Processing and degradation of foreign compounds is slower
than normal
• Xenobiotics could accumulate in adipose tissue
• Drugs: cimetidine, amphetamines, grapefruit (narengenin)
• Low exposure to toxins
ACETOMINOPHEN
BIOTRANSFORMATION
• 650 mg dose
• Urinary acetaminophen sulfate and acetaminophen
glucuronide
• Sulfate and B-vitamin status
ASPIRIN BIOTRANSFORMATION
• 650 mg dose
• O-hydroxyhippurate
• Glycine, pantothenic acid status
CONJUGATION PATHWAYS USED FOR
SPECIFIC COMPOUNDS
PHASE I/II RATIOS
• Bioactivation
• Impairment in phase II conjugation could lead to
accumulation of toxic intermediates
• Supplement with antioxidant nutrients
• Free radicals
• Cell injury
• DNA modification
• Haptens
FACTORS THAT INFLUENCE
DETOXIFICATION:
• Age
• Gender
• Diet and Lifestyle
• Environment
• Disease State
• Genetic polymorphisms
• Supplement use
• Intestinal Health
SUPPORTING DETOXIFICATION
• Co-factors and Nutrients

• Niacin, B6, glycine, NAC
• Antioxidants/protective nutrients
• vitamin C and E, zinc, lipoic acid
• Phytonutrients can trigger the activity of gene response elements

• Sulforaphane from broccolli
POLYMORPHYSIMS
•There are many known polymorphysims

that can affect detoxification.
• Example of effects;
Felton, J.S. What do diet-induced changes in phase I and
phase II enzymes tell us about prevetnion from exposure
to heterocyclic amines? Journal of Nutrition, Oct 2006.
136(10); 2683-4S
http://jn.nutrition.org/cgi/content/full/136/10/2683S

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3 PHASES OF

*Recall: Foreign chemicals are

• Xenobiotics may be naturally

• Xenobiotics may also be synthetic chemicals produced by humans.

Poisons are xenobiotics, but not all xenobiotics are poisonous.

Some xenobiotics cause toxicity by disrupting normal cell functions:

• Bind and damage proteins (structural,

• Bind and damage DNA (mutations)

• Bind and damage lipids

• React in the cell with oxygen to form

• Operates via Cytochrome P450 enzymes (Cyp)

• Bioactivation – adds an attachment site to the toxin - Requires

• Can result in a more toxic toxin

• Generates reactive oxygen species – thus ensuring antioxidant

P450 Enzyme Percent of Substrates

Cyp2C8,9,18 18% Warfarine, R-mephenytoin

Cyp1A2 13% Cafeine, aflatoxin B1

• Products of phase I detoxification are further metabolized

• Co-factors and Nutrients

• Phytonutrients can trigger the activity of gene response elements

•There are many known polymorphysims

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