Chapter 9 - Transformation of Contaminants Flashcards
the sum of all chemical processes of the body that modify endogenous or exogenous chemicals
biotransformation
focus area of toxicokinetics
- biotransformation
- absorption
- distribution
- storage
- elimination
host factors which affect biotransformation
- age
- sex
- existing disease
- genetic variability
- enzyme variability
- nutritional status
ability to metabolize a toxicant can vary with ____
age
Why would infants have limited britransformation?
they lack important enzymes
At what point do enzymes reach their optimal capacity for biotransformation in humans?
young adulthood
Why would the elderly have difficulties with biotransformation?
functional loss with aging
When are enzyme fluctions the highest in the lifetime of a human?
early adulthood
What is an example of gender-specific variability in biotransformation?
hormones
What is an impacting factor for biotransformation including minerals and vitamins?
nutritional status
What organ is very important for biotransformation and must be free from disease?
liver
biological catalysts and high-molecular weight proteins that allow biotransformation rates to proceed
enzymes
What is the disease called which infants are born with that converts the amino acid phenylalanine to tyrosine?
phenylketonuria
What is the treatment for individuals diagnosed with phenylketonuria?
- diet that restricts intake of foods containing phenylalanine
- use artificial sweeteners
** if not, mental retardation may result
When dealing withe substrate and reaction sites, what can cause a problem with biotransformation?
incorrect “proper fit” or induced fit
What do alcohols have in common?
share a common hydroxyl group
What enzyme metabolizes alcohol?
alcohol dehydrogenase
Once alcohol is metabolized, what can differ in its toxicity depending on the kind of alcohol metabolized?
metabolites differ
Chemicals are detoxified by which processes?
- rendering them less harmful
- making them more water soluble
What enzyme converts chloroform into phosgene?
P450
Which is more toxic?
chloroform or phosgene
phosgene
Different enzymes may ____ for the same toxicant.
compete
Aniline can form what two metabolites?
- phenylhdroxylamine
- p-aminophenol
enzyme that transforms analine into p-aminophenol
P450
enzyme that transforms aniline into phenylhydroxylamine
n-hydroxylase
Which is more toxic?
phenylhdroxylamine or p-aminophenol
phenylhdroxylamine
Which organ has the highest capacity for entering into reaction because of its high concentration of enzymes?
liver
Which organs have about a 5th of the biotransformation capcacity of the liver?
lungs and kidneys
intestines, placenta, skin
organelle where enzymes are found
endoplasmic reticulum
mixture of fragmented endoplasmic reticulum vesicles present in a cell homogenate after mechanical breakage
microsome
where are microsomes the most present in the body?
liver
what are other enzymes which are important for biotransformation of toxicants?
hydrolases, reductases, carboxylesterases
very large superfamily of hemoproteins found in all domains of life
cytochrome P450 (CYP450)
what metal group does CYP450 contain?
heme group
what are the three main types of phase 1 biotransforamtion reactions?
- oxidation
- reduction
- hydrolysis
loss of electrons, removal of hydrogen
oxidation
gain of electrons
reduction
splitting of a toxicant molecule into smaller molecules through the addition of water
hydrolysis
process which results in an increased ability to metabolize toxicants
enzyme induction
examples of phase 1 enzymes
- epoxide hydrolases
- flavin-containing monooxygenases
- amidases and esterases
- lipoxygenase
the metabolism of xenobiotics generates free radicals. this increases ____ and can result in cellular damage.
oxidative stress
xenobiotics that are done with phase 1 biotransformation reaction produce what?
intermediate metabolite
intermediate metabolites contain “polar handle” which as what groups?
- carboxyl
- amino
- hydroxyl
what are phase 2 reactions also known as?
conjugation reactions
- found in the cytosol and microsomal membrane bound
- homo- or hetero-dimeric enzymes
- mediate conjugation of electrophilic toxicants using glutathione GSH
- result is less reactive and more water-soluble that can be excreted
glutathione S-tranferase (GST)
tripeptide synthesized from its precursor amino acids gamma-glutamate, cysteine and glycine
glutathione (GSH)
glutathione and xenobiotic react via ____ to form glutathione-S-conjugate
GST
what is an example of the importance of balance between phase 1 and 2 reactions?
acetominophen toxicity
what is phase 1 of acetaminophen bioremediation?
mediated by cytochrome CYP2E1, produces hepatotoxic metabolite: NAPQI
what is phase 2 of acetaminophen biotransformation
used sulfotransferase and glucuronyl transferase to form the sulfate and glucuronide conjugation products of NAPQI that can be readily eliminated by the body
what can large does of acetaminophen do to the body?
it can overwhelm the conugating enzymes and result in toxicity
drug used in the treatment of tuberculosis and is detoxified through the addition of an acetyl grouo onto the molecule
isoniazid
mediated via N-acetyl-transferase
individuals that have a normal form of N-acetly-transferase can eliminate a dose of isoniazid can eliminate a dose by ____% in approximately ____ hour(s).
50, 1
“fast acetylators”
individuals who have a mutation for the enzyme N-acetly-transferase can eliminate a dose of isoniazid in ____ hour(s)
3
“slow acetylators”
individual response on a genetic level can leave an individual at greater risk of developing cancers, who are at most risk for this to happen?
slow acetylators
