Disease relevance of Cyp2c40

• The present study was performed to investigate the role of vasopressin in long-term regulation of UT1 and UT2 in neurogenic diabetes insipidus (Brattleboro) rats treated with a 7-day continuous infusion of [Arg(8)]-vasopressin (AVP), [deamino-Cys(1), D-Arg(8)]-vasopressin (dDAVP) or vehicle [1].

High impact information on Cyp2c40

• Recently, three types of urea transporters have been cloned, UT1 and UT2 from rat and rabbit kidney and HUT11 from human bone marrow [2].
• We report here the cloning of a novel urea transporter, designated UT1, from the rat inner medulla which is functionally and structurally distinct from the previously reported kidney urea transporter UT2 [3].
• Taken together, our data show that UT1 corresponds to the previously characterized vasopressin-regulated urea transporter in the apical membrane of the terminal IMCD which plays a critical role in renal water conservation [3].
• Studies of the rat genomic DNA further indicated that UT1 and UT2 are derived from a single gene by alternative splicing [3].
• UT1 expressed in Xenopus oocytes mediated passive transport of urea that was inhibited by phloretin and urea analogs but, in contrast to UT2, was strongly stimulated by cAMP agonists [3].

Biological context of Cyp2c40

• This cytochrome P-450 species (P-450 15 beta) has a total of 490 amino acid residues, and its deduced amino acid sequence as well as direct sequencing of the amino-terminal portion of the purified protein revealed its identity with P-450 i [4].
• Studies in Sprague-Dawley rats showed that restriction of water intake for 3 days results in upregulation of urea transporter (UT) mRNA in the inner stripe of outer medulla of the kidney (2.9-kb UT2) but not in the inner medulla (4.0-kb UT1) [1].
• Addition of cytochrome b5 to the reconstituted system enhanced the aminopyrine hydroxylation activities of P-450s UT-1, UT-2, PB-2, and PB-5 [5].
• Renal epithelia express at least two distinct urea transporter mRNAs, termed UT1 and UT2, that are derived from a single UT gene by alternative splicing [6].
• Thus, UT1 consists of two internally homologous portions that have most likely arisen by gene duplication [3].

Anatomical context of Cyp2c40

• Specific antibodies to isozyme 15 beta were used with a Western blot technique to demonstrate the virtual absence of the protein in male microsomes [7].
• Western blot analyses revealed clear differences in the expression of proteins immunologically related to cytochrome P-450 PB-1, and glutathione transferases B and X in parenchymal cells compared with the corresponding Kupffer and endothelial cells [8].
• In contrast, little or no phosphorylation of P-450 forms reactive with antibodies to P-450 PB-1 (gene IIC6), P-450 2c (gene IIC11), or P-450 PB-2a (gene IIIA1) was detected in the isolated hepatocytes under these incubation conditions [9].
• In vitro cytosol binding assays have shown the properties of binding of a novel steroid, ZK91587 (15 beta, 16 beta-methylene-mexrenone) in the brain of rats [10].
• Immunoblot analysis of rat liver microsomes with anti-P-450 PCN indicated that the amount of P-450 PCN increased 5- to 7-fold by the treatment with M79193, but no increase was observed in P-450 PB-1 (P450IIB1) or P-450 MC-1 (P-450IA1) [11].

Associations of Cyp2c40 with chemical compounds

• Therefore, it is concluded that P-450 isozymes 15 beta, 16 alpha, f, and PB-1 represent a subfamily within the phenobarbital related cytochrome P-450 gene family [12].
• Our studies reveal the role of vasopressin in long-term regulation of UT1 and UT2 expression during water restriction [1].
• The hydrophobicity values of the NH2-terminal sequences of P450 UT-1 and P450 UT-8 were lower than that of other forms [13].
• Lauric acid was also hydroxylated by P450 UT-1, UT-2, PB-1, PB-2, MC-1, IF-3 (P-450a) and DM, at the (omega - 1)-position only [14].
• In a reconstituted system with purified cytochromes P-450, P450 UT-1, UT-2 (P-450h), MC-1 (P-450d) and MC-5 (P-450c) effectively hydroxylated arachidonic acid at both the omega- and (omega-1)-position [14].

Regulatory relationships of Cyp2c40

• In situ hybridization further demonstrated that the UT2 signal is upregulated and spread along the descending thin limbs of loops of Henle and that UT1 signal is downregulated in the inner medullary collecting ducts in vasopressin-treated rats, with a greater response for dDAVP compared with the AVP-treated group [1].
• We previously demonstrated that renin release by kidney slices may be increased by beta-adrenergic agonists, and the present communication contains our results on the effects of 15 beta-blocking agents and angiotensin II on isoproterenol-stimulated renin release [15].

Other interactions of Cyp2c40

• Furthermore, P-450 15 beta is 47% similar to the major phenobarbital-inducible cytochrome P-450 in rat liver, P-450 b, while its structural similarity to P-450 c, P-450 pregnenolone-16a-carbonitrile, and P-450 lauric acid omega-hydroxylase is less than 30% [4].
• The NH2-terminal sequences of six forms of cytochrome P-450 (designated P450 UT-1, UT-2, UT-4, UT-5, UT-7 and UT-8) indicate that these cytochrome P-450 isozymes are of different molecular species [13].
• Slight changes in cytochromes P-450 UT-F, P-450 UT-I and P-450 PB-C were also observed under these conditions, but the biological significance is not known [16].
• Also, the N-demethylation activities of P-450s UT-1, PB-1, PB-2, and MC-1 were increased by cytochrome b5 [5].
• We believe that P450 UT-1, P450 UT-7 and P450 UT-8 are as yet unrecognized forms of cytochrome P-450 [13].

Analytical, diagnostic and therapeutic context of Cyp2c40

• Immunocytochemistry studies revealed that the UT1 and UT2 proteins are also modified in the same pattern as the transcript changes [1].
• Northern analysis showed that water restriction alone had no effect on the level of UT2 mRNA in vehicle-treated Brattleboro rats but UT2 mRNA markedly increased and UT1 mRNA modestly decreased after treatment with dDAVP [1].

References