Deck 11: Selective Genetic Sensitivity of Cells to Toxicants

Question 1

Why would polymorphisms of the OAT1B1 protein lead to liver cell hypersensitivity and polymorphisms of the MRP2 protein lead to liver cell hyposensitivity to the cholesterol lowering drug pravastatin?

Answer 1

OATP1B1 transported polymorphisms leads to increased plasma concentrations of the metabolite and toxicity of the statins. The opposite is true for those with polymorphisms encoding for a the multidrug resistance-associated protein 2.

Question 2

How can a CYP polymorphism OR a GSTM polymorphism lead to an increase in toxicity of a compound?

Answer 2

Increased activation of environmental or industrial toxicant activation (such as PAHs in cigarette smoke) or inability to conjugate toxic metabolites (such as the quinone imine of acetaminophen) may lead to increased toxicity and it may not be clear initially without genetic and metabolic analyses why the person or a specific population responded more strongly to a toxicant or toxicant mixture.

Question 3

People with polymorphisms in the ALDH1 gene don't enjoy liquor. Why?

Answer 3

The acetaldehyde they form from ethanol does not get metabolized rapidly to a less toxic form.

Question 4

Women with the BRCA1 or BRCA2 gene polymorphism/mutation are known to have poor outcomes for prevention of breast cancer. How might alterations of other genes lead to similar prognoses?

Question 5

Why do people with certain immune gene polymorphisms have dermal toxicity?