Question

Demerol (meperidine) is a drug used to relieve moderate to severe pain through inhibition of the NADH dehydrogenase complex. Explain why this drug does not completely abolish oxidative phosphorylation.

Answer 1

Most metabolic reactions occur under conditions where the reactions are freely reversible. reversible step of oxidative phosphorylation/electron transport occurs in the transfer of electrons from NADH to cytochrome c, with coincident conversion of ADP + Pi to ATP. Addition of product (ATP) favors reversal of the reaction (formation of NADH). Addition of NADH favors the forward reaction (production of ATP). The last step of electron transport (cytochrome oxidase), however, is essentially irreversible and can act as an excellent control point for electron transport. Cyt c oxidase is exclusively controlled by the availability of its substrate, reduced cyt c. Remember that reduced cyt c is produced as a result of the forward reaction. Thus, high NADH/low ATP concentrations favors formation of reduced cyt c, and the cyt oxidase reaction (increased electron transport). Resting individuals have high ATP concentrations, thus low reduced cyt c concentrations, and little electron transport. This control mechanism is called Acceptor Control, meaning that ultimately, one of the controls is ADP, the phosphoryl group acceptor. One complicating factor is that the critical ADP/ATP ratio is inside the mitochondrial matrix, whereas most ATP is used in the cytoplasm, and the inner mitochondrial membrane is impermeable to adenine nucleotides and Pi. Shuttle mechanisms must operate in order to move ADP and Pi inside the mitochondrion. It may be that transport of ADP and Pi across the mitochondrial membrane is the ultimate rate limiting step of oxidative phosphorylation.Hence Demerol (meperidine) drug does not completely abolish oxidative phosphorylation.

Meperidine (Demerol), crosses the brain blood barrier (BBB) and is metabolized in glial cells and serotonergic neurons by monoamine oxidase B (MAO-B) into 1-methyl-4-phenylpyridinium (MPP+). After cellular uptake, via dopamine transporter (DAT), MPP+ accumulates, preferentially, into mitochondria of DAergic neurons and inhibits complex I of the respiratory chain. This leads to production of ROS, disruption of the NP and adenosine triphosphate (ATP) depletion, suggesting a possible mechanism for nigral cell death.

Thank You!

Please rate this answer by clicking on "Thumbs Up" icon to support me, if this answer finds correct and helpful.