Biotransformation

Question 1

Depuration vs. Detoxification?

Answer 1

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

Question 2

What is a xenobiotic?

Answer 2

A chemical compound that is foreign to the body, or to an entire biological system

Question 3

What is the effect of starvation on NADPH and why is fasting/starvation not a good idea for biotransformation?

Answer 3

• 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.

Question 4

What is the main CYP in the liver?

Answer 4

CYP450-3A4

Question 5

What are some inhibitors of CYPs in the liver?

Answer 5

heavy metals, trauma, obesity, LPS, inflammation

Question 6

What effect do heavy metals have on glutathione production?

Answer 6

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.

Question 7

What are some major sites of toxin absorption and what are some types of cellular absorption?

Answer 7

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

Question 8

What is the main idea of biotransformation?

Answer 8

Conversion of lipid soluble xenobiotic into polar water soluble for excretion

Question 9

What are routes of excretion?

Answer 9

Urinary, biliary, pulmonary

Question 10

What are major storage sinks in the body for toxic substances?

Answer 10

Adipose, bones, liver, kidneys