Cytochrome antibiotics effect

Pinto AG, Wang YH, Chalasani N, et al. Inhibition of human intestinal wall metabolism by macrolide antibiotics effect of clarithromycin on cytochrome P450 3A4/5 activity and expression. Clin Pharmacol Ther 2005 77(3) 178-188. 

Cytochrome P-450 -copper m [MINERAL NUTRIENTS] (Vol 16) - [GASTROINTESTINALAGENTS] (Vol 12) - [PHARMACODYNAMICS] (Voll8) -effect ofmacrolides on [ANTIBIOTICS - MACROLIDES] (Vol3) -iron compounds [IRON COMPOUNDS] (Vol 14)... 

This scheme was supported and refined by examining the effects of specific inhibitors of individual steps in the electron-transport chain. If CO or CN was added in the presence of a reducing substrate and 02, all of the electron carriers became more reduced. This fits the idea that these inhibitors act at the end of the respiratory chain, preventing the transfer of electrons from cytochrome to 02. If amytal (a barbiturate) or rotenone (a plant toxin long used as a fish poison) was added instead, NAD+ and the flavin in NADH dehydrogenase were reduced, but the carriers downstream became oxidized. The antibiotic antimycin caused NAD+, flavins, and the b cytochromes to become more reduced, but cytochromes c, cx, a, and a3 all became more oxidized. The situation here is analogous to the construction of a dam across a stream When the gates are closed, the water level rises upstream from the dam, and falls downstream. The observation that antimycin did not inhibit reduction of UQ showed that the quinone fits into the chain upstream of cytochromes c, t i, a, and a3. 

Due to prokinetic effects in the colon, abdominal cramps and diarrhea occur in up to 15% of patients taking cisapride however significant problems are unusual. In addition, cisapride is metabolized by the hepatic cytochrome P450 CYP3 A4 enzyme. When coadministered with drugs that inhibit this enzyme (such as ketoconazole, fluconazole, macrolide antibiotics, and HIV protease inhibitors), significant increases in serum levels of cisapride may occur that rarely lead to QT prolongation on the ECG and serious cardiac arrhythmias. For this reason, cisapride was removed... 

Amacher DE, Schomaker SJ, Retsema JA. Comparison of the effects of the new azalide antibiotic, azithromycin, and erythromycin estolate on rat liver cytochrome P-450. Antimicrob Agents Chemother 1991 35(6) 1186-90. 

The classical inhibitor for the Q, site is another antibiotic, antimycin, that is produced by various species of Streptomyces. Antimycin blocks electron transfer from reduced Cyt 6(HP) to the oxidized quinone at the Qr site [see Pig. 12 (B, b)]. Binding of antimycin shifts the a-band of reduced Cyt ( (HP) from 562 to 564 nm in the Cyt bc complex. It has been demonstrated that antimycin also prevents the binding of the semiquinone radical in the Cyt 6(LP) domain. When both of these inhibitors are present, all electron transfers to and from either ofthe 6-cytochromes are blocked, a situation that has often been called a double kill of cytochrome 6 [see Fig. 12 (B, c)]. It should be noted, however, that even though myxothiazol and antimycin are very effective inhibitors for the be complexes, these compounds have virtually no inhibitory action on the A /complex, suggesting that some important structural differences must exist among these complexes. However, antimycin at a high concentration does inhibit cyclic electron flow around photosystem II, presumably by acting on a different protein. 

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