Primitive yeast yields secrets of human cholesterol and drug metabolism

sterol is essential for cell survival.

To show that Dap1 directly works with P450s and not through some other biochemical steps, Espenshades team tested the ability of human Dap1 protein to bind to four of the 57 known human P450 enzymes, essentially challenging Dap1 to bind to P450s that perform totally different functions in different cells as a way to see how far-reaching its control might be.

Dap1 locked on to all four P450s, including one required for clearing half of all known drugs from the body, another involved in making bile and one required for making natural steroid hormones in the adrenal glands.

Collectively, our experiments suggest that Dap1 acts as a common regulator of cytochrome P450s in mammals, says Espenshade.

Because Dap1 affects one particular P450 responsible for drug metabolism, Espenshade suspects that genetic variations in the genetic blueprint coding for Dap1 may provide clues to how and why different people react differently to certain drugs.

Understanding the molecular underpinnings of so-called pharmacogenetic variation will have a big impact on the future of medicine, he says.


Contact: Audrey Huang
Johns Hopkins Medical Institutions

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