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Angela B.

Telesforo

 OBJECTIVES:
1. To discuss the biotransformation of xenobiotics.
2. To explain the role of enzymes in the biotransformation of
xenobiotics.
3. To differentiate Phase 1 from Phase 2 reactions.
4. To compare the different reactions involved in Phase 1
and Phase 2 reactions.

What is Biotransformation?
 It is the conversion of chemicals to a more
water soluble compounds.
Xenobiotic – a chemical compound ( drug, pesticide,
carcinogen ) that is foreign to a living
organism.
Endogenous – chemical growing or originating from
within.

Substrate – substance to be catalyzed Substrate enzyme co-enzyme transformed product Ex. ethyl alcohol (CH3CH2OH) alcohol acetaldehyde dehydrogenase (CH3CHO) .

Phase 2 .addition of a functional group. Enzymes play a vital role in biotransformation  Transformation of Xenobiotics – either be beneficial or harmful  Depending on the dose and circumstances Phase 1 . .conjugation of the modified xenobiotic with another substance.

Conjugated Products  larger molecule than substrate Generally polar in nature ( water soluble ) Have poor ability to cross cell membranes .

carbamates ) ex.Phase 1 Reactions  HYDROLYSIS . hydrazines.reaction with the addition of water ( OH + H) ( esters. amines. procaine p-aminobenzoic acid + diethylaminoethanol .

Enzymes involved in Hydrolysis Carboxylesterases ( serum & tissues ) .detoxify electrophilic epoxides ( cause cellular toxicity and genetic mutations ) .generate pharmacologically active metabolites Cholinesterases .limit the toxicity of organophosphates Epoxide hydrolase .hydrolyze endogenous lipid compounds .

reduction reactions frequently result in activation of a xenobiotic than detoxification Ex. Azo reduction – nitrogen-nitrogen double bonds Nitro reduction – NO2 catalyzed by: * CYP450 * NADPH-quinone oxidoreductase .substrate gains electrons .occur with xenobiotics in which oxygen content is low . REDUCTION .

reactions in which substrate loses electrons * oxygenation *dehydrogenation *electron transfer . nitrobenzene + H2 aniline + O2 • OXIDATION .ex.

Enzymes involved in Oxidation Alcohol dehydrogenase primary alcohols secondary alcohols Aldehyde dehydrogenase aldehydes aldehydes ketones carboxylic acids ( NAD – cofactor ) .

including serotonin and some xenobiotics. secondary. Prostaglandin H synthetase ( cyclooxygenase ) arachidonic acid prostaglandins . and tertiary amines.Monoamine oxidase ( MAO ) oxidative deamination of primary.

found in hepatic ER microsomes .heme containing .Cytochrome P450 ( CYP ) .named in a species-specific manner .classified into subfamilies based on amino acid sequence identity .

Exposure to an environmental factor ( infectious disease or an inflammatory process ) . Factors that contribute to Decreased CYP enzyme activity 1. A genetic mutation – gives rise to the poor and intermediate metabolizer genotypes 2.suppresses CYP enzyme expression 3. Exposure to a xenobiotic .inhibits or inactivates a preexisting CYP enzyme .

one drug can impair the biotransformation of another – leading to an exaggerated pharmacologic or toxicologic response to the second drug . By inhibiting cytochrome P450.

Stimulation of preexisting enzyme by a xenobiotic Induction of cytochrome P450 by xenobiotics increases CYP enzyme activity . Gene duplication leading to over-expression of a CYP enzyme 2. Factors that contribute to Increased enzyme activity 1. Exposure to drugs and other xenobiotics that induce the synthesis of cytochrome P450 3.

By inducing cytochrome P450. . one drug can stimulate the metabolism of a second drug and thereby decrease or ameliorate its therapeutic effect.

hyperthyroidism. viral & bacterial infection. hypothyroidism ) It is possible that two or more CYP enzymes can contribute to the metabolism of a single compound. . Environmental Factors known to affect CYP levels  Medications  Foods  Social habits ( alcohol consumption. inflammation. cigarette smoking )  Disease status ( diabetes.

 Information on which human CYP enzyme metabolizes a drug can help predict or explain drug interactions  Inducers of cytochrome P450 increase the rate of xenobiotic biotransformation .

which compromises the therapeutic goal of drug therapy but does not cause an exaggerated response to the drug  P450 induction can cause pharmacokinetic tolerance whereby larger drug doses must be administered to achieve therapeutic blood levels due to increased drug biotransformation . P450 induction lowers blood levels.

. ( except methylation & acetylation)  Most conjugation enzymes are mainly located in the cytosol.Phase II Reactions CONJUGATION  Conjugations result in a large increase in xenobiotic hydrop0hilicity – greatly facilitates excretion of foreign chemicals.

 Glucuronidation Requires the cosubstrate uridine diphosphate- glucuronic acid ( UDP-glucuronic acid ) Reaction is catalyzed by UDPglucuronosyltransferases ( UGTs ) Endogenous substrates include bilirubin. steroid hormones. water-soluble metabolites Excreted from the body in bile or urine . and thyroid hormones Conjugates of are polar.

Cofactor availability can limit the rate of glucuronidation of drugs that are administered in high doses and are conjugated extensively. such as aspirin and acetaminophen .

 Sulfonation ( sulfate conjugation ) Catalyzed by sulfotransferases which produces a highly water-soluble sulfuric acid ester The cosubstrate for the reaction is 3’-phosphoadenosine-5’-phosphosulfate (PAPS) which is synthesized from inorganic sulfate Involves the transfer of sulfonate from PAPS to the xenobiotic Conjugates are excreted mainly in urine .

 Sulfonation is an effective means of decreasing the pharmacologic and toxicologic activity of xenobiotics .

S-Methylation . N-Methylation. Methylation Minor pathway of biotransformation Decreases the water solubility of xenobiotics Masks functional groups that might otherwise be conjugated by other enzymes The cosubstrate for methylation is S-adenosylmethionine ( SAM ) Methylation can also lead to increased toxicity O-Methylation.

facilitates their urinary excretion . such as isoniazid. Acetylation N-acetylation is a major route of biotransformation for xenobiotics aromatic amine hydrazine aromatic amide hydrazide N-acetylation of certain xenobiotics.

N-acetylation is catalyzed by cytosolic N-acetyltransferases ( NAT ) requiring the cosubstrate acetyl-coenzyme A ( acetyl-CoA ) NAT1 and NAT2 ( acetyltransferases in humans ) Slow NAT2 acetylators are predisposed to drug toxicities .

Drug toxicities Excessive hypotension from hydralazine Peripheral neuropathy from isoniazid and dapsone Systemic lupus erythematosus from hydralazine and procainamide Toxic effects of coadministration of anticonvulsant phenytoin with isoniazid .

glutamine and taurine  Aromatic hydroxylamine with the carboxylic acid group of amino acids serine and proline . Amino Acid Conjugation 2 pathways conjugation of xenobiotics containing:  Carboxylic acid group with the amino group of amino acids glycine.

Amino acid conjugates of xenobiotics are eliminated primarily in urine Conjugation of hydroxylamines with amino acids is catalyzed by cytosolic aminoacyl-tRNA synthetases and requires ATP .

glutathione is added to an activated double bond or strained ring system 1. and glutamic acid Catalyzed by a family of glutathione S-transferases that are present in most tissues Types of conjugation reactions Displacement reactions – glutathione displaces an electron-withdrawing group 2. . Addition reactions . cysteine. Glutathione conjugation Tripeptide glutathione comprises of glycine.

. and they can be converted to mercapturic acids in the kidney and excreted in urine  Conjugation with glutathione represents an important detoxication reaction : .because electrophiles are potentially toxic species that can bind to critical nucleophiles ( proteins & nucleic acids ) causing cellular damage and genetic mutations. Glutathione conjugates formed in the liver can be effluxed into bile and blood.

important in protecting cells against lipid and hemoglobin peroxidation Conjugation with glutathione enhances the toxicity of a xenobiotic by: 1.Glutathione is a cofactor for glutathione peroxidase. Being inherently toxic 3. Being degraded to a toxic metabolite . releasing a toxic metabolite 2.