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1.) fate of xenobiotic -- central role of metabolism
Uptake/Transport --------> Metabolism -------------> Excretion
Or Storage
2.) xenobiotic converted by 2-step process
(a.) Phase I biotransformations yield primary metabolite
-- oxidation
-- reduction
-- hydrolysis
(b.) Phase II conjugations yield product destined for excretion
-- glycine
-- glutamine
-- glutathione
-- glucuronate
3.) Phase I biotransformations
(a.) oxidations
-- hydroxylation
-- dealkylation
-- deamination
-- sulfoxide formation
(b.) reductions
-- hydrogenation
-- azo reduction
(c.) hydrolysis
-- spltting of ester bonds
-- splitting of amide bonds
4.) Phase II conjugations
(a.) primary metabolite/endogenous
substance/increased water solubility
5.) Phase I biotransformations
(a.) occur mostly in the liver
(b.) mediated by MFOs called cytochromes P450
(c.) occur in endoplasmic reticulum (liver microsomes)
(d.) mechanism
(e.) very broad range of substrates accomodated
-- aliphatic hydroxylation
-- aromatic hydroxylation
-- aliphatic epoxidation
-- aromatic epoxidation
-- N-oxidation
-- sulfoxidation
-- dealkylation
-- deamination
-- dehalogenation
6.) Phase II conjugations
(a.) occur in cytosol
7.) Phase I reactions generate reactive electrophiles
(a.) problem with halogenated alkenes or carbon tetrachloride
(b.) electrophiles react with nucleophiles - binding to cellular
(c.) endogenous antioxidants act as free radical scavengers
-- vitamin C
-- vitamin E
-- glutathione
(d.) reactive oxygen species can be handled enzymatically
-- superoxide dismutase
-- catalase
-- glutathione reductase
8.) Bacteria can use organic compounds as carbon source for growth
(a.) differentiate from detoxification
(b.) benzene conversion to acetaldehyde+pyruvate; yield CO2+H2O
(c.) general metabolic mechanisms
-- direct oxidative, reductive or hydrolytic attack
-- cometabolic transformation (TCE epoxidation, e.g.)
-- respiratory electron transfer
9.) Goals of bioremediation as a strategy in toxicity reduction