Toxicologic Mechanisms Flashcards
DMT1
divalent metal transporter 1
intestine luminal transporter for uptake of iron
upregulation in iron deficiency will also increase uptake of cadmium and lead
Constitutive Androstane Receptor and Pregnane X Receptor
induce CYP2B, 2C, and 3A
the most important human xenosensors in terms of drug–drug interactions.
First, CAR and PXR regulate several CYP enzymes (e.g., CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), conjugating enzymes (several UGTs andSULTs), and transporters (such as P-gp, MRP2, and MRP4).
Second, a large number of xenobiotics (drugs and the herbal preparations, St. John’s wort, and Yin Zhi Huang) and certain endobiotics (such as bilirubin, bile acids, and 1,25-(OH)2-D3) activate CAR and/or PXR.
Third, some of the genes regulated by CAR and PXR encode proteins with broad substrate specificities, such as CYP3A4 and P-gp, such that the induction mediated by CAR and PXR impacts the disposition of a large number of xenobiotics and certain endobiotics
expressed in relatively few organs—liver, small intestine, and colon—and in few cell lines. Both CAR and PXR are cytoplasmic nuclear receptors; both are activated by some of the same compounds, and both dimerize with RXRα to form DNA-binding proteins that recognize some of the same response elements,
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 320). McGraw-Hill Education. Kindle Edition.
alpha amanitin
mushroom toxin
inhibits RNA polymerase II
taken into hepatocytes by bile acid transporter
The most common method for detoxification of electrophiles
conjugation w/ glutathione
AhR receptor
induces CYP1
Paraquat
produces superoxide anion radicals
avermectins
avermectins block the transmission of electrical activity in invertebrate nerve and muscle cells mostly by enhancing the effects of glutamate at the glutamate-gated chloride channel that is specific to protostome invertebrates, with minor effects on gamma-aminobutyric acid receptors.
This causes an influx of chloride ions into the cells, leading to hyperpolarisation and subsequent paralysis of invertebrate neuromuscular systems
AMPK
AMP-activated protein kinase represents an adaptive cellular mechanism that responds to energy deficits to boost ATP production and limit ATP consumption (Hardie et al., 2006). The kinase is strongly activated by AMP,
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 114). McGraw-Hill Education. Kindle Edition.
Phenobarbital receptor
constitutively active receptor (CAR)
CAR is downregulated by proinflammatory cytokines
Excision Repair
Lesions that do not cause major distortion of the helix are removed by base excision, in which the altered base is recognized by a relatively substrate-specific DNA glycosylase. After its removal, the abasic sugar is replaced with the correct nucleotide by a DNA polymerase and is sealed in place by a DNA ligase.
Bulky lesions are removed by nucleotide-excision repair. An ATP-dependent nuclease recognizes the distorted double helix and excises a number of intact nucleotides on both sides of the lesion. The excised section of the strand is restored by insertion of nucleotides into the gap by DNA polymerase, using the complementary strand as a template. DNA ligase then forms a continuous strand.
Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.
Nonhomologous End Joining
repairs DSBs that may be formed when two SSBs occur in close proximity, or when DNA with SSBs undergoes replication. This repair system directly ligates broken strands without the need for a homologous template
more error prone than other types of DNA repair; however, it is unique in that it can operate in any phase of the cell cycle. It is also the mechanism of DSB repair in terminally differentiated cells such as neurons.
Klaassen, Curtis D.; Watkins, John B.. Casarett & Doull’s Essentials of Toxicology, Third Edition (Lange) . McGraw-Hill Education. Kindle Edition.
The most common nucleophilic detoxification reaction
acetylation…sulfonation, glucuronidation, methylation
Detoxification of free radicals
SODs convert O2- to HOOH
glutathione peroxidase of peroxisomal catalase convert HOOH to water
no effective protection against HO
PPARalpha
induces CYP4
Nanoparticle size
can enter target cells by passive diffusion, direct physical penetration, or active, receptor-mediated uptake by endocytosis or phagocytosis depending on their size and extent of agglomeration.
Small NPs appear to enter cells and organelles by passive diffusion.
Single walled carbon nanotubes (SWCNTs) have been shown to directly puncture bacterial cells leading to osmotic lysis and death.
Rigid, long, high-aspect ratio (needle-like) nanomaterials, similar to amphibole asbestos fibers (Palomaki et al., 2011), are recognized by macrophages; however, they undergo incomplete uptake or frustrated phagocytosis if they are longer than the macrophage diameter (Shi et al., 2011), resulting in impaired clearance from the lung, lysosomal disruption, and activation of the inflammasome resulting in the release of pro-inflammatory cytokines
Klaassen, Curtis D.. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th Edition (p. 1389). McGraw-Hill Education. Kindle Edition.
