浙江台州地区使用伊立替康人群UGT1A1基因多态性相关性研究

目的 研究浙江台州地区使用伊立替康（CPT-11）人群UGT1A1基因多态性和不良反应的相关性。方法 以使用含CPT-11化疗的132例台州地区汉族肿瘤患者为研究对象,取其外周血提取基因组DNA,进行UGT1A1基因多态性检测。结果 132例以CPT-11为基础化疗方案的台州地区肿瘤患者中UGT1A1*28 TA（6/6）野生型93例（70.45%）,TA（6/7）杂合突变型共36例（27.27%）,TA（7/7）纯合突变型仅3例（2.27%）;UGT1A1*6 G/G野生型共97例（73.48%）,G/A杂合突变型共35例（26.52%）,未找到A/A纯合突变型。UGT1A1*28非野生型（6/7+7/7）患者发生腹泻的概率显著高于野生型患者（P=0.040）。而粒细胞减少、血小板减少、血红蛋白减少与UGT1A1*28基因多态性无显著性差异。迟发性腹泻、粒细胞减少、血小板减少、血红蛋白减少水平与UGT1A1*6基因多态性无显著性差异。结论 浙江台州地区UGT1A1基因突变频率较高,TA（6/6）野生型人群相比TA（6/7）和TA（7/7）,CPT-11使用后的腹泻风险增加。建议浙江台州地区肿瘤患者使用CPT-11化疗前进行UGT1A1基因多态性检测,以预测患者对CPT-11的耐受性,保证化疗的顺利进行。     

UGT1A1基因与伊立替康致结肠癌患者腹泻及中性粒细胞减少的关系分析

目的分析尿苷二磷酸葡糖醛酸转移酶1A1 (UGT1A1)基因与伊立替康致结肠癌患者腹泻及中性粒细胞减少的关系。方法收集我院2017年5月至2018年4月入院治疗的60例结肠癌患者,均采用伊立替康治疗,分析并记录患者化疗中出现的腹泻及中性粒细胞减少情况,采集外周血,提取基因组DNA,测定UGT1A1基因多态性,研究基因型与2种不良反应的关系。结果 60例患者中,UGT1A1*28野生型50例,杂合突变型10例,突变纯合型无;UGT1A1*6野生型38例,杂合突变型20例,突变纯合型2例。UGT1A1*28、UGT1A1*6突变基因型患者腹泻、中性粒细胞减少发生率均高于野生型患者(P<0.05)。单因素分析显示,不同性别、年龄、转移器官数目、UGT1A1基因型、伊立替康剂量的结肠癌患者中,伊立替康致腹泻、中性粒细胞减少0～4级发生情况比较差异有统计学意义(P<0.05);不同ECOG评分者2种不良反应发生情况比较差异无统计学意义(P>0.05)。Logistic分析显示,UGT1A1*28基因型、UGT1A1*6基因型、伊立替康剂量是结肠癌患者伊立替康致腹泻、中性粒细胞减少的独立危险因素。结论结肠癌患者中,UGT1A1基因野生型最为常见,经伊立替康治疗后,UGT1A1*28、UGT1A1*6突变型患者的腹泻及中性粒细胞减少的风险明显增加,可为临床伊立替康不良反应的干预及用药选择提供理论依据。     

伊立替康不良反应与UGT1A1基因多态性关系的研究

目的:研究应用伊立替康化疗的患者不良反应的发生率及严重程度与UGT1A1基因启动子区多态性的关系。方法:选择56例我院晚期胃肠道肿瘤和小细胞肺癌患者,使用含伊立替康的方案化疗,观察并记录患者化疗中出现的不良反应;外周血中抽提基因组DNA,测定UGT1A1基因多态性,分析基因型与不良反应的关系。结果:42例患者(75.0%)UGT1A1*28为野生型TA6/6;13例患者(23.2%)为杂合突变型TA6/7;1例患者(1.8%)为纯合突变型TA7/7;UGT1A1*6野生型有44例(78.6%),杂合突变型有10例(17.9%),纯合突变型有2例(3.6%)。UGT1A1*28野生型、突变型患者发生Ⅲ度以上白细胞和/或中性粒细胞减少者分别为6、3例(14.3%vs.21.4%,P>0.01),其中纯和突变型患者发生Ⅲ度以上白细胞和/或中性粒细胞减少者为1例(100%);发生Ⅲ度以上腹泻者分别为6、2例(14.3%vs.14.3%,P>0.01),其中纯和突变型患者发生Ⅲ度以上腹泻为1例(100%)。UGT1A1*6野生型、突变型患者发生Ⅲ度以上中性粒细胞减少者分别为3、8例(6.8%vs.66.6%,P<0.01),发生Ⅲ度以上腹泻者分别为2、7例(4.5%vs.58.3%,P<0.01)。结论:晚期胃肠道肿瘤和小细胞肺癌患者中,UGT1A1基因野生型最为常见,杂合突变型次之,而纯合突变型很少见。TA7/7纯合突变型患者应用伊立替康化疗发生Ⅲ度以上白细胞和/或中性粒细胞减少和腹泻的风险增加,而TA6/7杂合突变型与TA6/6野生型相似,并不增加患者发生Ⅲ度以上中性粒细胞减少和腹泻的风险。UGT1A1*6突变型应用伊立替康化疗发生Ⅲ度以上中性粒细胞减少和腹泻的风险较野生型明显增加。     

伊立替康致3～4级中性粒细胞减少与UGT1A1基因多态性相关性的Meta分析

目的:系统评价UGT1A1基因多态性与伊立替康致3~4级中性粒细胞减少不良反应的相关性,为临床提供循证参考。方法:计算机检索中国期刊全文数据库、万方数据库、中文科技期刊数据库、Pub Med、EMBase、Science direct与Cochrane图书馆,收集UGT1A1*28和UGT1A1*6基因多态性与伊立替康致3~4级中性粒细胞减少的相关研究,对符合纳入标准的研究进行提取资料和质量评价,采用Rev Man 5.3统计软件进行Meta分析。结果:共纳入29项研究,合计2 408例患者。UGT1A1*28基因型分为野生型TA 6/6(UGT1A1*1/*1)和突变型TA 6/7(UGT1A1*1/*28)、TA 7/7(UGT1A1*28/*28),UGT1A1*6基因型分为野生型GG和突变型GA、AA。Meta分析结果显示,UGT1A1*28和UGT1A1*6突变型患者3~4级中性粒细胞减少发生率显著高于野生型,差异有统计学意义[UGT1A1*28:OR=1.92,95%CI(1.52,2.44),P<0.001;UGT1A1*6:OR=2.49,95%CI(1.46,4.26),P<0.001];伊立替康中、高剂量时UGT1A1*28和UGT1A1*6突变型患者3~4级中性粒细胞减少发生率显著高于野生型,差异有统计学意义[UGT1A1*28:OR=2.06,95%CI(1.57,2.70),P<0.001);UGT1A1*6:OR=1.92,95%CI(1.35,2.74),P<0.001];而伊立替康低剂量时UGT1A1*28和UGT1A1*6突变型患者3~4级中性粒细胞减少发生率与野生型比较差异无统计学意义[UGT1A1*28:OR=1.20,95%CI(0.70,2.08),P=0.51;UGT1A1*6:OR=3.19,95%CI(0.85,11.89),P=0.08]。结论:伊立替康的中、高剂量使用时,UGT1A1*28和UGT1A1*6突变基因会增加肿瘤患者重度中性粒细胞减少风险;但在低剂量时,基因多态性与中性粒细胞减少的相关性无明确的相关性。     

FOLFIRI方案治疗转移性结直肠癌96例观察

目的观察FOLFIRI方案治疗转移性结直肠癌的疗效、副反应及UGT1A1基因多态性与与副反应的相关性。方法对96例确诊的晚期结直肠癌患者,采用FOLFIRI方案治疗,观察近期疗效和副反应及UGT1A1基因多态性与副反应相关性。结果 96例患者用药后获得PR58例,SD 24例,PD 14例,无1例获得CR。ORR60.4%,DCR85.4%,所有患者均获随访,中位TTP 6.1月。主要毒副反应为骨髓抑制,其中中性粒细胞减少发生率为88.5%;脱发发生率较高,总发生率为83.3%;迟发性腹泻发生率为19.8%,均得到了有效的控制。检测UGT1A1基因多态性12例患者中,(TA)6/(TA)6UGT1A1*1/*1纯合野生基因型9例,发生腹泻为1例,为Ⅰ度。(TA)6/(TA)7UGT1A1*28/*1杂合基因型3例,发生腹泻2例,其中1例为Ⅲ度腹泻。结论 FOLFlRI方案是治疗常规化疗失败晚期结直肠癌的有效化疗方案,缓解率较高,迟发性腹泻和中性粒细胞减少为其主要不良反应。UGT1A1启动子区TATA盒基因多态性(TA)6/(TA)7杂合状态可以增加患者发生严重腹泻的风险。     

UGT1A1杂合突变与伊立替康所致不良反应的真实世界研究（英文）

为了研究某三甲肿瘤专科医院患者UGT1A1基因型分布,探索真实世界中患者UGT1A1基因多态性与服用伊立替康后的不良反应的相关性,我们回顾性分析2017年5月至2021年12月该院42例接受UGT1A1基因检测的患者资料,总结其中31例服用伊立替康后其血液学以及非血液学不良反应的发生情况。结果表明:UGT1A1^*28基因杂合突变率为21.9%,纯合突变率为4.9%, UGT1A1^*6基因杂合突变率为31.5%,未检测到纯合突变型;本研究中UGT1A1^*6及^*28杂合突变的患者较野生型患者血液学和非血液学不良反应未见显著性差异,血液学不良反应包括中性粒细胞减少、白细胞减少、血小板减少、血红蛋白减少,非血液学不良反应包括ALT/AST增高、ALP/GGT增高、胆红素增高、乏力、恶心、呕吐、迟发型腹泻; UGT1A1^*6和^*28双位点突变的患者出现迟发性腹泻的发生率为100%。研究表明, UGT1A1^*6和^*28双位点...     

UGT1A1多态性与小细胞肺癌伊立替康化疗疗效和不良反应的相关性

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1(UGT1A1)基因多态性与广泛期小细胞肺癌(SCLC)伊立替康联合顺铂(IP)方案治疗的疗效和不良反应的相关性。方法采用IP方案治疗广泛期SCLC患者54例,焦磷酸测序法测定UGT1A1基因多态性,比较不同基因型患者使用伊立替康的疗效和不良反应。结果 54例中,UGT1A1*28基因多态性分布:野生型(TA6/6)42例,杂合突变型(TA6/7)10例,纯合突变型(TA7/7)2例;UGT1A1*6基因多态性分布:野生型(G/G)41例,杂合突变型(A/G)8例,纯合突变型(A/A)5例。UGT1A1基因多态性与临床疗效无明显相关性(P>0.05)。UGT1A1突变型基因可增加患者发生迟发型腹泻及血小板减少的风险,而对中性粒细胞减少无明显影响。结论 UGT1A1基因多态性与伊立替康发生不良反应有关,但与其临床疗效无关。     

口腔黏膜拭子检测UGT1A1基因多态性并分析其与伊立替康药物不良反应的关系

目的探讨口腔黏膜拭子检测尿苷二磷酸葡糖苷酸转移酶1A1(UGT1A1)基因多态性的可行性,并分析UGT1A1基因多态性与伊立替康药物不良反应的关系。方法分别收集结直肠癌口腔黏膜和对应的外周血为检测标本共110例,提取标本中的DNA,以焦磷酸测序法检测UGT1A1基因多态性,记录标本对应的患者伊立替康化疗的不良反应,分析不同基因型患者使用伊立替康不良反应的发生率。结果 110例结直肠癌患者口腔黏膜拭子与对应外周血检测UGT1A1基因多态性完全一致。其中UGT1A1*28基因野生型TA6/6共85例(77.3%),杂合突变TA6/7共21例(19.1%),纯合突变TA7/7共4例(3.6%)。UGT1A1*6基因包括野生型G/G 82例(74.5%)、杂合突变G/A 23例(20.9%)、纯合突变A/A 5例(4.5%)。UGT1A1*28基因突变型明显增加3～4级腹泻及粒细胞减少的风险,UGT1A1*6基因突变型增加3级以上腹泻,但与粒细胞减少无显著相关性(P>0.05)。结论口腔黏膜拭子与外周血均可检测UGT1A1基因多态性,二者准确性相当。UGT1A1*28与UGT1A1*6可作为伊立替康相关严重不良反应的预测指标。     

尿苷二磷酸葡糖醛酸基转移酶1家族肽A基因多态性与伊立替康所致不良反应的相关性研究

目的探讨尿苷二磷酸葡糖醛酸基转移酶1家族肽A（UGT1A）基因多态性与抗肿瘤药伊立替康所致不良反应的相关性,为肿瘤患者个体化用药提供参考。方法研究对象为233名健康志愿者和196例应用伊立替康治疗的肿瘤患者。健康志愿者中男性169名,女性64名;平均年龄（25±5）岁。肿瘤患者中肠癌92例,宫颈癌45例,卵巢上皮细胞癌 59例;男性54例,女性142例;平均年龄（61±19）岁。采用焦磷酸测序法对2组受试者进行UGT1A1＊6、UGT1A1＊28、UGT1A3＊1、UGT1A3＊2、UGT1A3＊3、UGT1A3＊4 和UGT1A9＊22基因多态性检测,比较2组受试者UGT1A基因型突变频率,比较不同UGT1A基因型患者迟发性腹泻和白细胞和/或中性粒细胞减少发生率,采用Logistic 回归方法分析伊立替康致不良反应的危险因素,结果以相对危险度（OR）及95%置信区间表示。结果肿瘤患者UGT1A3＊2基因型突变频率明显低于健康志愿者（50.3%比68.5%,P=0.014）,而UGT1A3＊3基因型突变频率明显高于健康志愿者（26.0%比6.2%, P=0.001）。196例肿瘤患者Ⅱ～Ⅳ度迟发性腹泻发生率为48.5%（95例）,Ⅲ～Ⅳ度迟发性腹泻发生率为11.2%（22例）;Ⅲ～Ⅳ度中性粒细胞减少发生率为49.0%（96例）。UGT1A1＊28位点野生型纯合子（WW）基因型携带者Ⅱ～Ⅳ度和Ⅲ～Ⅳ度迟发性腹泻发生率均明显低于突变型杂合子（WM）＋突变型纯合子（MM）基因型携带者［Ⅱ～Ⅳ度：40.4%（57/141）比69.1%（38/55）,P=0.006;Ⅲ～Ⅳ度：5.7%（8/141）比25.5%（14/55）,P=0.001］;UGT1A9＊22位点WW基因型携带者Ⅱ～Ⅳ度迟发型腹泻发生率明显低于WM＋MM基因型携带者［26.2%（17/65）比47.6%（40/84）,P=0.006;26.2%（17/65）比51.1%（24/47）, P=0.0057］,未发现不同基因型患者之间Ⅲ～Ⅳ度中性粒细胞减少发生率差异存在统计学意义。Logistic回归分析显示UGT1A基因型与迟发性腹泻的发生相关（OR=5.657,95%置信区间为4.782～7.245,P=0.039）。结论UGT1A1＊ 28 和UGT1A9＊ 22基因多态性可增加伊立替康所致迟发性腹泻的风险。     

UGTlAl＊6和＊28基因多态性与伊立替康毒性关系研究

目的探讨UGTlA＊6和828基因多态性与伊立替康治疗癌症患者的不良反应发生率及严重程度之间的关系,为临床个体化用药提供依据。方法采用PCR扩增目的基因片段,通过直接测序法分析85例接受伊立替康治疗的肺癌或消化道肿瘤等患者的UGTlAl。6和”28基因型。同时观察应用伊立替康治疗中出现的不良反应。结果85例患者中,UGTlAl＊6野生型G／G有46例（54．1％）,杂合突变型G／A有30例（35．3％）,纯合突变型A／A有9例（10．6％）;UGTlAl＊28野生型TA6／6有64例（75．3％）,杂合突变型TA6／7有19例（22．4％）,纯合突变型TA7／7有2例（2．3％）。85例肿瘤患者中,＊6突变型（G／A和A／A）可以增加发生3级以上腹泻（12．8％vs2．2％,P〈0．05）的风险;UGTlAl＊6和＊288突变型个体,3级以上中性粒细胞减少（P〉0．05）、白细胞减少（P〉0．05）等的发生率与野生型相比有升高趋势。结论中国患者中UGTlAl＊28突变分布频率较低,而UGTlAl＊6突变分布频率较高;UGTlAl＊6基因突变可以显著增加患者发生3级以上腹泻的风险,而’6或’28突变型个体其他不良反应的发生率有增加趋势。     

Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors

The sphingolipid sphingosine-1-phosphate (S1P) acts on five subtypes of G-protein- coupled receptors, termed S1P(1) (formerly endothelial differentiation gene-1 [Edg-1]), S1P(2) (Edg-5), S1P(3) (Edg-3), S1P(4) (Edg-6) and S1P(5) (Edg-8), and possibly several other "orphan" receptors, such as GPR3, GPR6 and GPR12. These receptors are coupled to different intracellular second messenger systems, including adenylate cyclase, phospholipase C, phosphatidylinositol 3-kinase/protein kinase Akt, mitogen-activated protein kinases, as well as Rho- and Ras-dependent pathways. Consistently with this receptor multiplicity and pleiotropic signaling mechanisms, S1P influences numerous cell functions. S1P(1)1, S1P(2) and S1P(3) receptors are the major S1P receptor subtypes in the cardiovascular system, where they mediate the effects of S1P released from platelets, and possibly other tissues (such as brain). Thus S1P(1) and S1P(3) receptors enhance endothelial and vascular smooth muscle cell proliferation and migration, playing a key role in developmental and pathological angiogenesis. In contrast, S1P(2) receptors inhibit migration of these cell types, probably because of their unique stimulatory effect on a GTPase-activating protein inhibiting the activity of Rac. S1P receptors can also cause relaxation and constriction of blood vessels. The former effect is mediated by pertussis toxin-sensitive receptors (possibly S1P(1)) located on the endothelium and stimulating phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase (eNOS). The vasoconstricting effect of S1P is likely to be mediated by S1P(2) and/or S1P(3) receptors, via Rho-Rho-kinase, and is more potent in coronary and cerebral blood vessels. Finally, S1P also protects endothelial cells from apoptosis through activation of phosphatidylinositol 3-kinase/Akt/eNOS via S1P(1) and S1P(3) receptors. The variety of these effects, taken together with the existence of multiple receptor subtypes, provides an abundance of therapeutic targets that currently still await the development of selective agents.     

Antimykobakterielle 1-Phenyl-1-alkylaminoalkane

Antimycobacterial 1-Phenyl-1-alkylaminoalkanes Synthesis and testing for antimycobacterial properties (M. tuberculosis H 37 Ra, Middlebrook-7H9-broth) of 1-phenyl-1-alkylaminoalkanes, which differ from antimycobacterial N-alkylbenzylamines by an additional alkyl chain in α-position, is described. By variation of both alkyl chains and introduction of one or two Cl-substituents in the aromatic ring the activity increases up to an optimum within the homologous series. Overstepping optimal lipophilicity or ramification of the alkyl chains decrease activity. Compounds 19, 20, 33-35, 51-53, 61-63, 65-67, 70-73, 96 and 102 - 104 inhibit the growth of M. tuberculosis in concentrations of 2 to 4 μg/ml.     

Sulfation of iodothyronines by human sulfotransferase 1C1 (SULT1C1)*

Sulfation is an important component of human thyroid hormone metabolism. The role of the human sulfotransferase 1C1 (SULT1C1) is not known. Because SULT1C1 is present in the adult thyroid, intra-thyroidal sulfation of thyroid hormones and their metabolites might occur. We tested this hypothesis by determining the ability of recombinant human SULT1C1 to catalyze iodothyronine sulfation. Apparent K(m) values for 3,3',5-triiodothyronine (T(3)), 3, 3'-diiodothyronine (3,3'-T(2)), 3',5',3-triiodothyronine (rT(3)), and 3,3',5,5'-tetraiodothyronine (T(4)) with SULT1C1 were 28.7, 10.3, 10.2, and 59.3 microM, respectively. Thermal stability and responses to inhibitors also were tested with T(3) as the substrate. Enzyme aliquots were measured simultaneously to determine SULT1C1 substrate preferences at optimal iodothyronine concentrations. SULT1C1 activity obtained with T(3) was used as 100%, and the activities with 3,3'-T(2), rT(3), T(4), and 3,5-diiodothyronine (3, 5-T(2)) were 614, 314, 25, and 4%, respectively. We report for the first time the characterization of human SULT1C1 with T(3) and the preferences of the enzyme for various iodothyronines. The presence of SULT1C1 in the adult thyroid gland raises the possibilities that the enzyme can contribute to intraglandular thyroid hormone processing and iodide reutilization.     

Preferential induction of CYP1A1 and CYP1B1 in CCSP-positive cells.

Both benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are potent ligands of aryl hydrocarbon receptors (AhR). Although animal studies indicate that both compounds induce pathological changes in the peripheral lung, the specific cell type involved remains unclear. Clara cells, expressing Clara cell specific protein (CCSP) and abundant in cytochrome P450, are nonciliated bronchiolar epithelial cells in the peripheral lung. Here we explore the hypothesis that CCSP-positive Clara cells are highly responsive to AhR ligands and are the primary cell type involved in BaP- and TCDD-induced toxicities. The responsiveness to AhR ligands was evaluated by measuring the respective mRNA and protein levels of cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) using real-time RT-PCR and immunocytochemistry assays. Two in vitro models were used: primary cultures of human small airway epithelial (SAE) cells and rat lung slice cultures. In the presence of calcium, human SAE cells differentiated into CCSP-positive cells. BaP- and TCDD-induced mRNA and protein levels of CYP1A1 and CYP1B1 levels were significantly elevated in CCSP-positive cell cultures. Similarly, AhR mRNA and protein levels were increased in CCSP-positive cell cultures, as determined by real-time RT-PCR and Western blot analysis. When rat lung slice cultures were treated with BaP or TCDD for 24 h, CYP1A1 and CYP1B1 proteins were strongly induced in Clara cells. These results indicate that, in the peripheral lung of both rats and humans, CCSP-positive cells (Clara cells) may be more sensitive to AhR ligands than other cell types.     

间质作用因子1通过正调控窖蛋白1抑制FBJ-S1-H的迁移性

目的证明间质作用因子(stromal interaction molecule1,Stim1)在FBJ诱导的小鼠骨肉瘤细胞中的抑癌作用。方法在Stim1高表达的FBJ-S1-H细胞采用Stim1以siRNA干扰技术得到Stim1沉默的几株S1-H单克隆细胞株,通过细胞行为学方法和RT-PCR技术对其mRNA进行研究,通过明胶酶谱法对细胞基质金属酶活性进行研究。结果通过细胞行为学方法证明,Stim1的沉默提高了细胞的迁移性,通过对mRNA表达的研究发现,Stim1沉默引起了多种基因表达的变化,其中包括基质金属酶9(matrix mexalloprotelnase 9,MMP-9)的升高,窖蛋白(caveolinl,Cav1),甾醇调控因子Srebf1的降低等,提高单克隆细胞中的Cav1含量可以使细胞迁移性降低。结论实验结果证明在FBJ-S1-H细胞中,Stim1能够抑制细胞的移动性,沉默Stim1的表达能够提高细胞的迁移性。     

Phenotype of the Cyp1a1/1a2/1b1-/- triple-knockout mouse

Crossing the Cyp1a1/1a2(-/-) double-knockout mouse with the Cyp1b1(-/-) single-knockout mouse, we generated the Cyp1a1/1a2/1b1(-/-) triple-knockout mouse. In this triple-knockout mouse, statistically significant phenotypes (with incomplete penetrance) included slower weight gain and greater risk of embryolethality before gestational day 11, hydrocephalus, hermaphroditism, and cystic ovaries. Oral benzo[a]pyrene (BaP) daily for 18 days in the Cyp1a1/1a2(-/-) produced the same degree of marked immunosuppression as seen in the Cyp1a1(-/-) mouse; we believe this reflects the absence of intestinal CYP1A1. Oral BaP-treated Cyp1a1/1a2/1b1(-/-) mice showed the same "rescued" response as that seen in the Cyp1a1/1b1(-/-) mouse; we believe this reflects the absence of CYP1B1 in immune tissues. Urinary metabolite profiles were dramatically different between untreated triple-knockout and wild-type; principal components analysis showed that the shifts in urinary metabolite patterns in oral BaP-treated triple-knockout and wild-type mice were also strikingly different. Liver microarray cDNA differential expression (comparing triple-knockout with wild-type) revealed at least 89 genes up- and 62 genes down-regulated (P-value < or = 0.00086). Gene Ontology "classes of genes" most perturbed in the untreated triple-knockout (compared with wild-type) include lipid, steroid, and cholesterol biosynthesis and metabolism; nucleosome and chromatin assembly; carboxylic and organic acid metabolism; metal-ion binding; and ion homeostasis. In the triple-knockout compared with the wild-type mice, response to zymosan-induced peritonitis was strikingly exaggerated, which may well reflect down-regulation of Socs2 expression. If a single common molecular pathway is responsible for all of these phenotypes, we suggest that functional effects of the loss of all three Cyp1 genes could be explained by perturbations in CYP1-mediated eicosanoid production, catabolism and activities.