Mackie J E, Back D W, Hamilton J W, Marks G S
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Biochem Pharmacol. 1991 Jul 15;42(3):475-83. doi: 10.1016/0006-2952(91)90308-r.
A series of compounds that increase the activity of delta-aminolevulinic acid synthase (ALAS) in chick embryo hepatocyte cultures were studied for their effects on steady-state levels of mRNA for ALAS and phenobarbital-inducible cytochrome PB1 P450. N-Ethylprotoporphyrin IX (N-EtPP), which is believed to lower heme levels by inhibition of ferrochelatase (FC), had little effect on steady-state ALAS mRNA levels. 3,5-Diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4- isobutylpyridine (4-isobutyl DDC), which is believed to lower heme levels by repetitive destruction of the heme moiety of cytochrome P450, increased steady-state levels of ALAS mRNA levels approximately 2-fold. 3,5-Diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine (4-ethyl DCC) which inhibits FC activity and destroys the heme moiety of cytochrome P450, increased ALAS mRNA levels approximately 4-fold. A combination of N-EtPP and 4-isobutyl DDC produced a synergistic increase in ALAS mRNA levels to approximately 6-fold over control levels. The synergistic increase in ALAS activity observed previously with this combination can be explained, at least in part, by a synergistic increase in ALAS mRNA levels. Other porphyrinogenic agents, which function as mechanism-based inactivators of cytochrome P450 and elevate ALAS activity, were found to elevate ALAS mRNA. These compounds included 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS), 2,4-diethyl-2-methyl-1,2-dihydroquinoline (DMDQ), and 2,2,4-trimethyl-1,2,dihydroquinoline (TMDQ). The elevation of ALAS mRNA by these porphyrinogenic agents is probably due to their lowering of cellular heme levels by a combination of ferrochelatase inhibition and repetitive destruction of the heme moiety of cytochrome P450. The lowering of heme levels should result in an enhancement of ALAS mRNA half-life as it has been demonstrated by others that heme shortens the half-life of ALAS mRNA. It was of interest that some of these drug treatments also caused an elevation in steady-state levels of cytochrome PB1 P450 mRNA; the exception was TTMS, which along with its analogue 3-(2-phenylethyl)-4-methylsydnone (PEMS), did not alter cytochrome PB1 P450 mRNA levels. Increases in steady-state levels of cytochrome PB1 P450 mRNA subsequent to increases in steady-state levels of ALAS mRNA were observed with 4-ethyl DDC, 4-isobutyl DDC, DMDQ, and TMDQ. The data obtained with N-EtPP and a combination of N-EtPP and 4-isobutyl DDC on cytochrome PB1 P450 mRNA levels do not support the contention that heme functions as a positive regulator of cytochrome P450 gene expression.
研究了一系列能增加鸡胚肝细胞培养物中δ-氨基乙酰丙酸合酶（ALAS）活性的化合物对ALAS及苯巴比妥诱导的细胞色素PB1 P450的mRNA稳态水平的影响。N-乙基原卟啉IX（N-EtPP）据信通过抑制亚铁螯合酶（FC）降低血红素水平，对ALAS mRNA稳态水平影响甚微。3,5-二乙氧羰基-1,4-二氢-2,6-二甲基-4-异丁基吡啶（4-异丁基DDC）据信通过反复破坏细胞色素P450的血红素部分降低血红素水平，使ALAS mRNA稳态水平增加约2倍。3,5-二乙氧羰基-1,4-二氢-2,6-二甲基-4-乙基吡啶（4-乙基DCC）抑制FC活性并破坏细胞色素P450的血红素部分，使ALAS mRNA水平增加约4倍。N-EtPP与4-异丁基DDC联合使用使ALAS mRNA水平协同增加至对照水平的约6倍。先前观察到的该联合使用时ALAS活性的协同增加至少部分可由ALAS mRNA水平的协同增加来解释。其他作为细胞色素P450基于机制的失活剂并提高ALAS活性的卟啉生成剂被发现可提高ALAS mRNA水平。这些化合物包括3-[2-(2,4,6-三甲基苯基)硫代乙基]-4-甲基-3-亚甲基异恶唑（TTMS）、2,4-二乙基-2-甲基-1,2-二氢喹啉（DMDQ）和2,2,4-三甲基-1,2-二氢喹啉（TMDQ）。这些卟啉生成剂使ALAS mRNA水平升高可能是由于它们通过抑制亚铁螯合酶和反复破坏细胞色素P450的血红素部分来降低细胞血红素水平。血红素水平降低应会导致ALAS mRNA半衰期延长，因为其他人已证明血红素会缩短ALAS mRNA的半衰期。有趣的是，其中一些药物处理还导致细胞色素PB1 P450 mRNA稳态水平升高；例外的是TTMS，它及其类似物3-(2-苯乙基)-4-甲基-3-亚甲基异恶唑（PEMS）未改变细胞色素PB1 P450 mRNA水平。在4-乙基DCC、4-异丁基DDC、DMDQ和TMDQ处理后，观察到ALAS mRNA稳态水平升高后细胞色素PB1 P450 mRNA稳态水平也升高。用N-EtPP以及N-EtPP与4-异丁基DDC联合处理得到的数据关于细胞色素PB1 P450 mRNA水平并不支持血红素作为细胞色素P450基因表达的正调节因子这一观点。
