Inhibition of Cytochrome P-450 Activity in Rat Liver Microsomes by Ratinoids = Retinoid가 흰쥐肝組織 microsome 內 Cytochrome P-450 活性 抑制作用

국문 초록 (Abstract)

Retinoid에 의한 Cytochrome P-450-dependent 반응이 억제되는 억제 기전과 Kinetics를 측정하였다.
β-naphthoflavone(β-NF), Phenobarbital(PB) 및 methylcholanthrene(MC)로 유도된 흰쥐 간 microsome과 retinoid로는 retinol, retinyl acetate 및 β-carotene을 사용하였다. β-NF, PB 및 MC로 유도된 micrisome으로 p-nitroanisole-O-demethylation과 ethoxycoumarin-O-deethylation활성과 polycyclic hydrocarbon B(a)P hydroxylation이 억제되는 것을 in vitro 실험으로 관찰하였다. 또한 cytochrome P-450에 대한 Kinetics를 측정한 결과 cytochrome P-450이 기질에 대한 Km value는 retinoid의 존재로 증가하였다. 이는 기질 결합 부위에 대하여 변화되고 경쟁적이라는 억제 기전을 나타내는 것이다.
Retiyl acetate를 경구 투여한 in vitro 실험에서 mixed-function oxidase인 p-nitroanisole-O-deme-thylation과 UDP-glicironyl transferase의 활성이 감소되고 또한 electron transfer system 성분인 cytochrome P-450 및 b_5 그리고 NADPH- 및 NADH-cytochrome C(P-450) reductase의 활성이 감소되였다. Retinoid는 cytochrome P-450-dependent반응에 억제자이고기질에 대한 결합을 방해하는 억제저로써 작용한다. Biphasic Kinetics는 이런 억제 반응이 복잡하다는 것을 나타내고 즉, B(a)P hydroxylation이 isozyme-specific 하지 않다는것을 나타냈다.

다국어 초록 (Multilingual Abstract)

The kinetic characteristics and mechanism of retinoids inhibition of cytoch-rome-mediated reactions were examined in rat liver microsomes, using retinol, retinylacetate and β-carotene. Retinoids inhibited the p-nitroanisole-O-demeth-ylation and ethoxycoumarin-O-deethylation in β-NF, PB, and MC-induced micr-osomes. Retinoid also inhibited benzo(a)-pyrene hydroxylation. Specific steps in the P-450 reaction pathway were tested for sensitivity to retinoid inhibition. The Km values of the P-450 substrates tested were increased in the presence of retinoid; competition for and/or alteration of the substrate binding site contributes to the mechanism of inhibition.
The treatments with retinoids have reduced the rates of O-demethylation for p-nitroanisole, the activities of UDP-glucuronyl transferase and of elec-tron transfer components. β-NF-, PB-and MC-induced microsomes. Retinoids are inhibitors of P-450 reactions and interfere with substrate binding. The biphasic kinetics emphasize the complexity of this inhibition, which, in the case of the substrate B(a)P, does not appear to be isozyme-specific.