Depuration vs. Detoxification?
Depuration: The action/process of freeing something of impurities, preferred term for the removal of xenobiotics by the body
Detox: The process of transforming a toxic substance into a non-toxic substance
What is a xenobiotic?
A chemical compound that is foreign to the body, or to an entire biological system
What is the effect of starvation on NADPH and why is fasting/starvation not a good idea for biotransformation?
- NADPH is one component of phase 1 detox, the generation of it and UDP-glucuronate (phase 2) are closely connected to carb metabolism of the liver
- Normal conditions, in well-fed state, pentose phosphate pathway (PPP) provides sufficient NADPH for biotransformation
- Increased biotransformation stimulates PPP (which shifts intermediates of malate + glucose-6-phosphate to NADPH generation from gluconeogenesis)
- Under starvation conditions, NADPH for biotransformation can only be produced at the expense of gluconeogenesis.
What is the main CYP in the liver?
CYP450-3A4
What are some inhibitors of CYPs in the liver?
heavy metals, trauma, obesity, LPS, inflammation
What effect do heavy metals have on glutathione production?
GSH deficiency: Glutathione production (cysteine dependent) is on a circadian clock: nadir at about 6 pm. GSH cycles between oxidation, being cycled back by glutathione reductase; if a heavy metal is present, then replenishment cannot occur.
What are some major sites of toxin absorption and what are some types of cellular absorption?
Major sites:
- Ingestion - GI, mostly small intestine
- Inhalation - lungs
- Dermal absorption - skin (worse w/ eczema, soaking in water)
Types of absorption:
- Simple Diffusion
- Passage through pores
- Specialized transport systems
What is the main idea of biotransformation?
Conversion of lipid soluble xenobiotic into polar water soluble for excretion
What are routes of excretion?
Urinary, biliary, pulmonary
What are major storage sinks in the body for toxic substances?
Adipose, bones, liver, kidneys
