BIOCHEMISTRY II: XENOBIOTIC METABOLISM
HARPER’S BIOCHEMISTRY TRANS (31ST ED)
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OUTLINE
I. INTRODUCTION
A. DEFINITIONS
B. CLINICAL IMPORTANCE
B.1. MAIN XENOBIOTICS OF MEDICAL IMPORTANCE
II. PHASES
A. PHASE 1
A.1. CYTOCHROME P450
A.1.1. NOMENCLATURE
A.1.2. ISOFORMS OF CYTOCHROME P450
A.1.3. OVERLAPPING SPECIFICITY
B. PHASE 2
B.1. GLUCURONIDATION
B.2. SULFATION
B.3. GLUTATHIONE CONJUGATION
B.3.1. GLUTATHIONE S-TRANSFERASES
B.3.2. TRANSPORT OF GLUTATHIONE CONJUGATES
B.3.3. GLUTATHIONE ROLES IN METABOLISM
B.4. OTHER REACTIONS
B.4.1. ACETYLATION
B.4.2. METHYLATION
III. RESPONSES TO XENOBIOTICS
A. TOXIC EFFECTS
B. IMMUNOLOGIC EFFECTS
C. CARCINOGENIC EFFECTS
IV. REFERENCES
V. APPENDIX
I. INTRODUCTION
A. DEFINITIONS
Xenobiotics
• Xenos [G.
xenos
, foreign]
• Wide variety of compounds that are foreign to the body
• Naturally occurring compounds in plant foods
• Synthetic compounds in medicines
• Food additives
• Environmental pollutants
Xenobiotic metabolism
• Liver – where most compounds are metabolized
• process of detoxification
o However, it includes metabolites of compounds
that are generally inert, harmless, or biologically
inactive
• Importance?
o Inactive prodrug may be activated to an active
compound
o Carcinogenic/mutagenic compounds may be
produced from an initially inactive precursor
FIGURE 1. XENOBIOTIC METABOLISM
B. CLINICAL IMPORTANCE
1. Pharmacology
2. Therapeutics
3. Toxicology
4. Development of transgenic microorganisms and plants
(contain antioxidants etc) containing genes that encode
enzymes
• can be used to render potentially hazardous
pollutants harmless
5. Transgenic organisms may be used for biosynthesis of drugs
and other chemicals
B.1. MAIN XENOBIOTICS OF MEDICAL IMPORTANCE
• Drugs
• Chemical carcinogens
• Naturally occurring compounds that have found their way
into our environment
o polychlorinated biphenyls (PCBs)
o insecticides
o pesticides
FIGURE 2. PHASES IN XENOBIOTIC METABOLISM
II. PHASES
Occurs in two phases:
1. Hydroxylation
o Major reaction
o Catalyzed by enzymes that are monooxygenases
or cytochromes P450
2. Conjugation
o Enzymes can catalyze wide range of other
reactions:
▪ Deamination
▪ Dehalogenation
▪ Desulfuration
▪ Epoxidation
▪ Peroxygenation
▪ Reduction
▪ Other enzymes (and their reactions)
• Esterases – hydrolysis
A. PHASE 1
• renders compounds more reactive
• Introduces groups that can be conjugated with glucuronic
acid, sulfate, acetate, glutathione, or amino acids in phase 2
metabolism
• Produces polar compounds which can be excreted in urine
(water-soluble)
• Some cases occur wherein biologically inactive compounds
→ biologically active
o In these instances, the original xenobiotics are
referred to as prodrugs or procarcinogens
• Sometimes additional phase 1 reactions occur
o Example: further hydroxylation converts active
compounds into less active or inactive forms
prior
to conjugation
▪ however, in some cases, the conjugation
is what converts the active products of
phase 1 reactions to inactive compounds
A.1. CYTOCHROME P450
• Hydroxylate a wide variety of xenobiotics in phase 1
metabolism
• There are at least 57 cytochrome p450 genes in the human
genome (SEE APPENDIX TABLE 2)
• It is a heme enzyme
• “450” = absorption peak at 450 nm
