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The cytochrome P450s play a unique role in the metabolism of xenobiotics. Characteristics which allow a vast number of foreign compounds to be metabolized by a limited number of enzymes include broad substrate specificity and broad regioselectivity. Because of their importance in both the metabolism and toxicity of drugs and environmental contaminants, efforts are being made to use computational methods to predict these biotransformation pathways. This review describes the recent progress towards the prediction of the tertiary structures of the various P450s and the determination of the electronic characteristics of substrates which determine their tendency to be oxidized by the P450s.
We have developed a human B-lymphoblastoid cell, designated h2D6v2, which expresses high levels of CYP2D6 cDNA. Microsomal P450 contents of 160 pmol mg-1 protein were observed. NADPH-fortified microsomes exhibited a substantial capacity to hydroxylate the prototype CYP2D6 substrates bufuralol and debrisoquine. Kinetic parameters, apparent Km, turnover number, Ki for quinidine inhibition and stereospecificity of bufuralol hydroxylation, observed with the human lymphoblast expressed enzyme were similar to those observed in human liver microsomes or purified liver CYP2D6 proteins. Therefore, the human lymphoblast expressed material appears to faithfully reflect the authentic protein. Relative to control cells, h2D6v2 cells were more sensitive to the cytotoxicity and mutagenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), supporting our previous observation with a cell line expressing lower levels of CYP2D6. h2D6v2 microsomes were capable of metabolizing NNK and NNK metabolism and mutagenicity were markedly inhibited by the addition of quinidine, a CYP2D6 inhibitor. h2D6v2 cells coupled with control cells, represent a useful in vitro system for studying xenobiotic metabolism by the clinically important, polymorphic CYP2D6. The human lymphoblast system offers the desirable ability to couple metabolic transformation studies with toxicological endpoints such as cytotoxicity and mutagenicity.
The human CYP3A P450 family, composed of at least four highly homologous genes, is expressed prominently in the liver. To investigate the expression of CYP3A family members individually, we prepared oligonucleotides specific for each CYP3A mRNA and used Northern blot analysis and/or polymerase chain reaction to examine RNA from adult and fetal liver for variation in expression of the CYP3A forms during development. We found that CYP3A4 (P450NF) mRNA, was only detectable by Northern blot postnatally, was highly variable (10-fold) among the adult samples, and, unlike its rat counterparts (CYP3A1/2), was not influenced by gender. In contrast, CYP3A7 (HFLa) mRNA, a form previously thought to be confined to fetal liver, was found in all tested samples of fetal liver as well as in seven of 13 adult livers (54%). CYP3A5 (HLp2), an mRNA also found in all the fetal samples, was detected in three of these 13 adults (23%) and two of these three co-expressed CYP3A7 mRNA. CYP3A5 and CYP3A7 are expressed at similar levels in fetal liver from either gender. Moreover, CYP3A7 expression in fetal liver appears less variable (< 2.5-fold) than CYP3A4 in adults. We conclude, that contrary to prevailing views, expression of CYP3A7 in the liver is not restricted to the fetus but rather represents a second CYP3A form selectively expressed in adults.
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