Study Set Content:
Phase II-
cytosol
(blank)and other foreign chemicals may not
always be an innocuous biochemical event leading
to detoxification and elimination of the compound.
Metabolism of drugs
Several compounds have been shown to be metabolically
transformed to reactive intermediates that are (blank) various organs
toxic
Such toxic reactions may not be apparent at low levels of
exposure to parent compounds when alternative
detoxification mechanisms are not yet overwhelmed or
compromised and when the availability of endogenous detoxifying co-substrates (GSH Glutathione, glucuronic
acid, sulfate) is
not limited
co-substrates
(GSH Glutathione, glucuronic
acid, sulfate)
Take note, when these endogenous substrate becomes
exhausted just like in the case of Glutathione (tripeptide)
being exposed to chemical toxins like alcohol, cadmium
exposure or the patient has a disease like parkinson’s
disease this will lead to decrease in
glutathione activity
is the body’s master anti-oxidant.
Glutathione
when these resources are exhausted, the toxic pathway
may prevail, resulting in overt organ toxicity or
carcinogenesis.
acetaminophen (paracetamol)-
induced hepatotoxicity
▪ Active metabolite:
acetyl-p-
benzoquinone imine (NAPQI)
Acetaminophen, an analgesic antipyretic drug, is
quite safe in therapeutic doses (1.2 g/d for an
adult). It normally undergoes (blank)to the corresponding conjugates, which
together make up 95% of the total excreted
metabolites.
glucuronidation and
sulfation
The alternative (blank)
pathway accounts for the remaining 5%
P450-dependent GSH conjugation
When acetaminophen intake far exceeds
therapeutic doses, the glucuronidation and
sulfation pathways are saturated, and the P450-
dependent pathway becomes increasingly
important
Little or no hepatotoxicity results as long as hepatic
GSH is available for
conjugation
Little or no hepatotoxicity results as long as hepatic
GSH is available for conjugation. However, with
time, (blank) is depleted faster than it can be
regenerated, and a reactive, toxic metabolite
accumulates.
hepatic GSH
In the absence of intracellular nucleophiles such
as GSH, this reactive metabolite ( N -
acetylbenzoiminoquinone) reacts with nucleophilic
groups of cellular proteins, resulting in
hepatotoxicity
The chemical and toxicologic characterization of the electrophilic
nature of the reactive acetaminophen metabolite has led to the
development of effective antidotes:
cysteamine and N -acetylcysteine.
Administration of (blank) (the safer of the two)
within 4–16 hours after acetaminophen overdosage has
been shown to protect victims from fulminant hepatotoxicity and death.
N -acetylcysteine
Administration of GSH is not effective because it does not
cross (blank) readily.
cell membranes
The dose and frequency of administration required to achieve
effective therapeutic blood and tissue levels vary in different
patients because of individual differences in
drug distribution
The dose and frequency of administration required to achieve
effective therapeutic blood and tissue levels vary in different
patients because of individual differences in drug distribution and
rates of
drug metabolism and elimination.
