Chem toxicology

High porosity of renal and hepatic endothelium. – Specialized transport into cell. – Accumulation in cell organelles. – Reversible intracell

Plasma protein binding. – Specialized barriers. – Storage sites. – Intracellular protein binding. – Specialized export from cells.

e.g., reabsorption from kidney proximal tubule. – e.g., enterohepatic recirculation.

Formation of electrophiles, free radicals, redox‐active reactants. – Each can be detoxified before reaching target.

Molecules with an electron deficient atom or group. – Form covalent bonds with cellular nucleophiles.

Formed by accepting an electron, losing an electron, or homolytic fission of a covalent bond. – Can act as hard electrophiles, abstract hydr

Initiallyresultsintheformationofsuperoxideanionradical(O2‐). • Throughaseriesofnon‐enzymaticstepsotherformsofreactive oxygen are formed: –

High intracellular concentration. – Rapid synthesis by cytosolic enzymes. – High concentration of glutathione transferases.

Separate physiological pool. – High concentration in the matrix. – Responsible for oxygen radical detoxification

Saturation of enzyme system. • Consumption of enzyme cofactors. • Depletion of cellular nucleophiles. • Direct inactivation of detoxificatio

DNA, RNA, protein are the most common targets. – Target must possess reactivity, accessibility, and a critical function. – Many toxicants c

Noncovalent binding. • Covalent binding. • Hydrogen abstraction. • Electron transfer. • Enzymatic reactions.

No specific receptor involved. – Xenobiotic dissolves in membrane or associates with protein non‐specifically.

Xenobiotic binds to a specific membrane or cell receptor. – Can range from low to very high affinity. – Can activate or block receptor.

Ligands activate receptor to induce multiple effects. Normal physiologic ligand still unknown.

Electrophile is the attacking species. • Soft electrophiles preferentially react with soft nucleophiles and vice‐versa. • Most common

Common with neutral free radicals, converts target to a radical. – Can mediate crosslinking of biomolecules.

e.g., oxidation of hemoglobin Fe+2 to Fe+3 by nitrite (methemoglobinemia)

Mostly seen with biological toxins that have enzymatic activity, e.g., N‐glycosidase activity of ricin

Inappropriate receptor activation. • Blockade of receptor action (more common). • Alteration of protein target molecule structure and/or fun

Crosslinking. – Fragmentation/Oxidation.

Modified molecule is seen as “foreign” by the body. – Can be antibody or cell mediated immune response