Submitted to:Dr. Afrasim MoinAsst ProfessorDept. Of PharmaceuticsJSSCP,mysore

Presented by:Rajendra Prasad.P.C

1st M.Pharm

Industrial Pharmacy

JSSCP, Mysore

Definition:-Bioactivation is defined as: Enzymatically

formed metabolites, which are more reactive than the

mother substance and excreted metabolites.

OR

Formation of highly reactive metabolites (from relatively

inert chemical compounds) which interact with the

tissues to precipitate one or more of the several forms

of toxicities such as carcinogenesis is called as

bioactivation or toxicological activation.

The most significant toxicological effects of

xenobiotics are reactive metabolites are:-

can react with nucleophilic sites

SH groups (glutathione, cysteine)

NH2 and – COOH groups (DNA, RNA, proteins)

Imbalance between formation and detoxification of reactive metabolites can arise from: enzyme induction (increased biotransformation and

formation of reactive metabolites)

high dose of xenobiotic

depletion of cellular defence mechanisms.

saturation of non-toxic pathways

Compounds Reactive pathway or intermediate product

Factors increasing toxicity

Acetaminophen N-hydroxylation Sulphate and GSH depletion

Acetyl hydrazine N-hydroxylation Aflatoxin B Epoxidation Further metabolism Benzene Epoxidation Benzo[a]pyrene Epoxidation PCB Epoxidation GSH depletion Tetrachlorcarbon Free radicals Reductive metabolism Halothane Free radicals Reductive metabolism Parathion Oxidation with

sulphur formation

Electrophiles

Free radicals

Electrophiles: - are species deficient in electron pair.

The enzyme system through which they generated is

cytochrome P-450. Carbon, nitrogen or sulphur

containing compounds can be metabolically activated to

yield electrophiles.

Important electrophiles are:Epoxides;-e.g., epoxide of benzo(a)pyrene present

in cigarette smoke which causes cancer.

Hydroxylamines, nitroso and azoxy derivatives, nitrenium ions and elemental sulphur.

Mechanism:- The mechanism by which electrophiles precipitate

toxicity is through covalent binding to nucleophilic tissue components such as macromolecules(proteins, nucleic acids, and lipids) or low molecular weight cellular constituents.

Covalent binding to DNA is responsible for

carcinogenicity and tumour formation.

The body’s defence against electrophiles is their

inactivation by conjugation with glutathione, the most

abundant cellular nucleophile with –SH group.

An e.g. of tissue toxicity due to electrophiles is

hepatotoxicity of paracetamol metabolites

Free radicals are species containing an odd number of electron. They may be positively charged (cation radical), negatively charged (anion radical) or neutral radical.R+ R- R

Cation radical Anion radical neutral radical

Free radicals are generally formed via NADPH cytochrome P-450 reductase or other flavincontaining reductases.

Xenobiotics that on metabolic activation yield free radicals are Quinone’s, aryl amines, nitro aryls and carbon tetrachloride.

Endogenous compounds such as epinephrine and DOPA can also generate free radicals.

Most free radicals are organic.They provide toxicity by peroxidation of cellular

components.

An important class of free radicals is inorganic free

radicals such as hydrogen peroxide and superoxide

anion.

These oxidative moieties can cause tremendous

tissue damage leading to mutations or cancer.

The potential toxicity of free radicals is far greater than

that of the electrophiles.

Cellular defence mechanisms against free radicals

include control imposed by membrane structure,

neutralization by glutathione, control exerted by non-

enzymatic antioxidant scavengers such as vitamin A,

E and C and enzymatic inactivation of oxygen derived

free radicals.

Generation of reactive metabolites is indicated by

modification in enzyme activities, formation of

glutathione conjugates and depletion in tissue levels

of glutathione. Since the availability of glutathione in

the body determines the threshold for toxic response,

thiols(e.g., N-acetyl cysteine) can be used to treat

poisoning by drugs such as paracetamol that yield

reactive metabolites.

Benzo(a)pyrene Aromatic epoxidation Lung cancer

Aflatoxin B1 Olefin epoxidation Hepatic cancer Thalidomide Hydrolytic cleavage of

lactam Teratogenesis

Chlorinated hydrocarbons

Oxidative dehalogenation

Nephrotoxicity

BIOPHARMACEUTICS AND

PHARMACOKINETICS BY

D.M.BRAHMANKAR,SUNIL B.JAISWAL.P.NO-

189-191

www.sciencedirect.com

Biopharmaceutics & Pharmacokinetics by Milo

Gibaldi, 4th edition

THANK YOU