Effects of the aqueous extract fromSalvia miltiorrhizaBge on the pharmacokinetics of diazepam and on liver microsomal cytochrome P450 enzyme activity in rats

Drug interactions are key reasons for adverse drug reactions and attrition from market. Major infectious diseases causing morbidity/mortality in Ghana are malaria, tuberculosis, and HIV/AIDS. In this study, plant medicines commonly used to treat/manage these diseases in Ghana were investigated for their potential to modulate rat cytochrome P450 enzyme activities. Fluorescence and high-performance liquid chromatography–based assays were used to assess effects of antimalarial plant medicines, Fever (FEV), Mal-TF (MAL), and Kantinka terric (KT); anti-TB medicines, Chestico (CHES), CA + ST Pains + HWNT (TF), and Kantinka herbatic (KHB); and anti-HIV/AIDS medicines, Wabco (WAB), AD + T/AD (LIV) and Kantinka BA (KBA) on rat liver microsomal cytochrome P450 enzyme activities. Effects of medicines on rat biochemical and hematological parameters were also assessed. Generally, the medicines altered microsomal CYP1A1/1A2, CYP2B1/2B2, CYP2C9, and CYP2D6 activities. Only KBA elicited an increase (80%) in CYP1A1/1A2 activity. FEV, MAL, CHES, WAB, and LIV strongly inhibited the enzyme activity. All the medicines significantly inhibited CYP2C9 (24%-80%) activity. CYP2D6 activity increased after treatment with MAL, KBA, LIV, and TF. Also, MAL, WAB, LIV, KHB, and CHES increased CYP2B1/2B2 activity, while KT decrease the activity. Generally, the medicines altered liver function in the rats. Cholesterol levels declined after KBA treatment only. White and red blood cell counts, hemoglobin and hematocrit levels were significantly reduced in KT- and KBA-treated rats. Our results suggest that use of the medicines could have implications for drug interactions and safety, particularly if the medicines are administered over prolonged periods. Further investigations are imperative to establish clinical relevance of these results.

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Suppressive effect of accumulated aluminum trichloride on the hepatic microsomal cytochrome P450 enzyme system in rats

Food and Chemical Toxicology ◽

10.1016/j.fct.2012.09.035 ◽

2013 ◽

Vol 51 ◽

pp. 210-214 ◽

Cited By ~ 16

Author(s):

Yanzhu Zhu ◽

Yanfei Han ◽

Hansong Zhao ◽

Jing Li ◽

Chongwei Hu ◽

...

Keyword(s):

Cytochrome P450 ◽

Enzyme System ◽

Suppressive Effect ◽

Cytochrome P450 Enzyme ◽

Microsomal Cytochrome ◽

P450 Enzyme ◽

Microsomal Cytochrome P450 ◽

Cytochrome P450 Enzyme System ◽

Aluminum Trichloride

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Characterization of Medicago truncatula (barrel medic) hydroperoxide lyase (CYP74C3), a water-soluble detergent-free cytochrome P450 monomer whose biological activity is defined by monomer–micelle association

Biochemical Journal ◽

10.1042/bj20051667 ◽

2006 ◽

Vol 395 (3) ◽

pp. 641-652 ◽

Cited By ~ 17

Author(s):

Richard K. Hughes ◽

Eric J. Belfield ◽

Mylrajan Muthusamay ◽

Anuja Khan ◽

Arthur Rowe ◽

...

Keyword(s):

Enzyme Activity ◽

Cytochrome P450 ◽

Medicago Truncatula ◽

Water Soluble ◽

Hydroperoxide Lyase ◽

Cytochrome P450 Enzyme ◽

Cytochrome P450 Enzymes ◽

P450 Enzyme ◽

Detergent Micelles

We describe the detailed biochemical characterization of CYP74C3 (cytochrome P450 subfamily 74C3), a recombinant plant cytochrome P450 enzyme with HPL (hydroperoxide lyase) activity from Medicago truncatula (barrel medic). Steady-state kinetic parameters, substrate and product specificities, RZ (Reinheitszahl or purity index), molar absorption coefficient, haem content, and new ligands for an HPL are reported. We show on the basis of gel filtration, sedimentation velocity (sedimentation coefficient distribution) and sedimentation equilibrium (molecular mass) analyses that CYP74C3 has low enzyme activity as a detergent-free, water-soluble, monomer. The enzyme activity can be completely restored by re-activation with detergent micelles, but not detergent monomers. Corresponding changes in the spin state equilibrium, and probably co-ordination of the haem iron, are novel for cytochrome P450 enzymes and suggest that detergent micelles have a subtle effect on protein conformation, rather than substrate presentation, which is sufficient to improve substrate binding and catalytic-centre activity by an order of magnitude. The kcat/Km of up to 1.6×108 M−1·s−1 is among the highest recorded, which is remarkable for an enzyme whose reaction mechanism involves the scission of a C–C bond. We carried out both kinetic and biophysical studies to demonstrate that this effect is a result of the formation of a complex between a protein monomer and a single detergent micelle. Association with a detergent micelle rather than oligomeric state represents a new mechanism of activation for membrane-associated cytochrome P450 enzymes. Highly concentrated and monodispersed samples of detergent-free CYP74C3 protein may be well suited for the purposes of crystallization and structural resolution of the first plant cytochrome P450 enzyme.

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