2 Flashcards
(18 cards)
what are specific drug transporter proteins?
(ABC transporters)
organs?
transmembrane proteins
containing nucleotide binding domains for the binding and hydrolysis of ATP
found in organs like GIT, kidneys, and brain
how many specific drug transporter proteins are there?
3 most important?
49 known ABC transporters
most important = ABC-B1, ABC-C2, ABC-G2
what is tissue localisation?
when highly lipophilic substances build up in adipose tissue more than other tissues
ingested PPBs causes build up of phospholipids
metabolism at the absorption site - epidermis
significant metabolic activity occurs in epidermis
may metabolise toxicants as they are absorbed
metabolism at the absorption site - GIT
gut bacteria may alter toxicant
pH may affect chemical structure
natural carcinogen (cycasin) is hydrolysed by gut bacteria after oral administration
what is the first pass effect?
toxicants absorbed from GIT are transported to liver via hepatic portal vein
metabolism in liver may alter the structure of compound - more or less toxic
what is cytochrome P450 (CYP450)?
where is it located? what role does it play?
membrane associated haem proteins
present in most tissues
located on inner membrane of mitochondria or ER
substrate in enzyme rxns
terminal oxidase enzymes in ETC
what is biotransformation?
where does it occur?
metabolic transformation or metabolism of the toxicant
occurs in liver, lungs, stomach, kidney, intestine + skin
what can occur to substances in biotransformation?
can be activated to a toxic form - become reactive to biomolecules such as DNA, RNA, proteins + lipids
or inactivated to non-toxic form
metabolites in biotransformation are…?
usually more water soluble and polar = more excretable
- process mediated by phase 1 and 2 metabolising enzymes = detoxification / bio inactivation
- sometimes metabolites are more toxic than the parent compounds = bio activation
biotransformation phase 1 reactions?
oxidation (CYP450 + NADPH)
reduction (reverse run of alcohol dehydrogenase)
hydrolysis
= degradation rxns
—> metabolites or phase 2
biotransformation phase 2 reactions?
conjugation
synthesis
= production of compound
—> metabolites
what are toxicants bound to?
where are they stored?
usually stored in non-target organs
plasma proteins (albumin) can bind toxicants
storage in adipose tissue?
lipophilic compounds
e.g. pesticides, dioxins, PCBs
simple dissolution or possible conjugation with fatty acids
rapid mobilisation of fat stores
storage in bones?
chemicals similar to calcium, fluorine, lead, strontium
bone mineral is a major storage site of these toxicants
storage in blood?
plasma proteins
storage in liver and kidney?
they have higher capacity for binding chemicals
e.g. 30 mins after single administration of lead, the toxicant conc in liver is 50x higher than that in plasma
rate of excretion of toxicants?
an accepted indicator is the toxicant’s half life
= the time required to remove 50% of the toxicant from the blood stream
secreted as parent chemicals
