Differential Modulation of CYP2E1 Activity by cAMP-Dependent Protein Kinase upon Ser129Replacement

Oesch-Bartlomowicz, Barbara; Padma, P. R.; Becker, Roger; Richter, Bernd; Hengstler, Jan G.; Freeman, Joel; Wolf, Charles; Oesch, Franz

doi:10.1006/excr.1998.4120

Cited by 43 publications

(37 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Post-translational modification of other P450 cytochrome enzymes occurs due to phosphorylation events initiated by high cAMP levels (OeschBartlomowicz et al, 2001;Oesch-Bartlomowicz and Oesch, 2002). As Atlantic salmon ovarian P450 arom has serine residues present (Andersson et al, 2001) and as serine residues are particularly susceptible to phosphorylation (Oesch-Bartlomowicz et al, 1998), an effect of this type is possible in salmon.…”

Section: Discussionmentioning

confidence: 99%

Maintenance of Atlantic salmon (Salmo salar) at elevated temperature inhibits cytochrome P450 aromatase activity in isolated ovarian follicles

Watts

Pankhurst

King

2004

General and Comparative Endocrinology

View full text Add to dashboard Cite

Atlantic salmon (Salmo salar) broodstock were transferred from natural (12-16 o C) to controlled temperatures of 14, 18 or 22 o C for 3 months during vitellogenesis. Fertility and survival were significantly reduced in eggs from broodstock held at 22 o C relative to 14 or 18 o C. Endocrine mechanisms were disrupted after only one month at 22 o C, as evidenced by decreased plasma vitellogenin (Vtg) and increased plasma testosterone (T) levels and, at later stages, decreased levels of plasma 17β-estradiol (E 2 ) . In vitro incubations of isolated ovarian follicles were carried out at monthly intervals, with follicles exposed to human chorionic gonadotropin, N, 2-0-dibutyryladenosine 3,5-cyclic monophosphate, and the gonadal steroid precursors 17-hydroxyprogesterone, androstenedione and T. After one month of exposure to controlled temperature, T synthesis was generally enhanced in response to all treatments at all temperatures, but E 2 synthesis was inhibited at 22 o C, suggesting temperature impairment of cytochrome P450 aromatase (P450 arom ) synthesis or activity. The effect became less marked as follicles matured suggesting that temperature sensitivity is stage dependent. The results of this study suggest that the inhibitory effects of elevated temperature on E 2 and Vtg synthesis, and subsequent egg development found in the present and earlier studies, arise at least partly, from temperature modulation of P450 arom .

show abstract

Section: Discussionmentioning

confidence: 99%

Maintenance of Atlantic salmon (Salmo salar) at elevated temperature inhibits cytochrome P450 aromatase activity in isolated ovarian follicles

Watts

Pankhurst

King

2004

General and Comparative Endocrinology

View full text Add to dashboard Cite

show abstract

“…To our knowledge, this finding provides the first evidence that phosphogroup(s) in UGT operationally control pH of catalysis and that phosphoserine-432 in UGT1A7 controls its alkaline pH activity. Mutations at PKA phosphorylation sites in mouse CYP2E1 have also shown changes in substrate preference (21).…”

Section: Effects Of T73a T202a and S432g Mutations On Ugt1a7 And Ugmentioning

confidence: 99%

Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity

Basu

Kovářová

Garza

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

UDP-glucuronosyltransferase (UGT) isozymes catalyze detoxification of numerous chemical toxins present in our daily diet and environment by conjugation to glucuronic acid. The special properties and enzymatic mechanism(s) that enable endoplasmic reticulum-bound UGT isozymes to convert innumerable structurally diverse lipophiles to excretable glucuronides are unknown. Inhibition of cellular UGT1A7 and UGT1A10 activities and of [ 33 P]orthophosphate incorporation into immunoprecipitable proteins after exposure to curcumin or calphostin-C indicated that the isozymes are phosphorylated. Furthermore, inhibition of UGT phosphorylation and activity by treatment with PKC-specific inhibitor peptide supported PKC involvement. Coimmunoprecipitation, colocalization by means of immunofluorescence, and crosslinking studies of PKC and UGT1A7His revealed that the proteins reside within 11.4 Å of each other. Moreover, mutation of three PKC sites in each UGT isozyme demonstrated that T73A͞G and T202A͞G caused null activity, whereas S432G-UGT1A7 caused a major shift of its pH-8.5 optimum to 6.4 with new substrate selections, including 17␤-estradiol. S432G-UGT1A10 exhibited a minor pH shift without substrate alterations. PKC involvement was confirmed by the demonstration that PKC overexpression enhanced activity of UGT1A7 but not of its S432 mutant and the conversion of 17␤-[ 14 C]estradiol by S432G-UGT1A7 but not by UGT1A7. Consistent with these observations, treatment of UGT1A7-transfected cells with PKC-specific inhibitor peptide or general PKC inhibitors increased 17␤-estradiol catalysis between 5-and 11-fold, with parallel decreases in phosphoserine-432. Here, we report a mechanism involving PKC-mediated phosphorylation of UGT such that phosphoserine͞threonine regulates substrate specificity in response to chemical exposures, which possibly confers survival benefit.PKC ͉ PKC inhibitors ͉ detoxifying enzymes ͉ UDP-glucuronosyltransferase mutants ͉ immunofluorescence M ammalian UDP-glucuronosyltransferase (UGT) isozymes detoxify numerous lipid-soluble chemicals, including metabolites, such as neurotoxic bilirubin, as well as dietary and environmental agents͞toxins and medicines (1). UGT facilitates detoxification of chemicals by attaching glucuronic acid molecules to form water-soluble, readily excretable glucuronides. Failure to attach glucuronic acid (glucuronidation) to toxins allows high levels to accumulate in tissues, causing deleterious effects, including mutations of genes and the development of cancer (2). Mutations in UGT1 genes lead to lethal hyperbilirubinemic Crigler-Najjar disease (3) and to toxic tissue levels of the commonly used analgesic acetaminophen (Tylenol) in rats (4). The fact that a limited number of UGT isozymes facilitate excretion of a vast number of structurally diverse chemicals suggests a mechanism evolved to confer flexibility on an isozyme to metabolize multiple toxins. Because UGTs are bound to membranes of the endoplasmic reticulum (ER) that cause difficulties associated with purification and s...

show abstract

“…4) When the metabolism of xenobiotics, generally toward intoxicification, is accompanied by the formation of toxic intermediates, the host defense systems should be mobilized to maintain homeostasis by either inducing or suppressing the enzyme activities. In addition to the well-characterized xenobiotic-elicited induction, the regulatory mecha-*To whom correspondence should be addressed: School of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.…”

Section: Introductionmentioning

confidence: 99%

Comparative Study on the Mode of Action of Chlorinated Ethylenes on the Expression of Rat CYP Forms.

Nakahama

Mizuno

Otsuka

et al. 2001

JOURNAL OF HEALTH SCIENCE

View full text Add to dashboard Cite

Many environmental chemicals (xenobiotics), including polychlorinated ethylenes (CEs), are known to be metabolically intoxicated via the formation of hazardous intermediates (referred to as biological activation), while the expression of metabolic enzymes might be interfered with by xenobiotics at various stages in a system to minimize their adverse biological effects on the host animals. Three CEs, i.e., tetrachloroethylene (PCE), trichloroethylene (TCE) and 1,1-dichloroethylene (1,1-DCE), were comparatively studied for their effects on the in vivo expression of CYP forms, which are responsible for their metabolic activation, as well as organospecificities between the liver and lung. Furthermore, their effects on the expression of CYP forms were studied in the animals simultaneously administered with phenobarbital (PB), known as an inducer of CYP2B. Individual CEs were administered intraperitoneally at 0.5 g/kg alone or simultaneously with PB (80 mg/kg/d) to 7-week-old male Wistar rats weighing about 200 g. The testosterone hydroxylase activities, CYP2B-and 2E1-mRNA, and CYP2B-and 2E1-proteins were measured 24 hr after the treatment. Testosterone 2β-hydroxylase (2βTSH) and 16βTSH activities are attributable to the functions of CYP3A2, and CYP2B plus CYP3A2, respectively. The induction of hepatic CYP2B in the PB-treated animals might be masked by the suppressive effect of CYP3A2 in terms of the 16βTSH activity, while the pulmonary 16βTSH activity was confined to the function of CYP2B, which was insensitive to the inducing effect of PB. The inhibition of hepatic 16βTSH activity was observed exclusively in the presence of 1,1-DCE, especially in PBcoadministered animals, suggesting the preferable suppression of CYP2B. In the lung, however, PCE suppressed the 16βTSH activity in the absence of PB. The expression levels of hepatic CYP2B mRNA and protein were significantly lowered by 1,1-DCE in the presence of PB. Concerning hepatic CYP2E1, no alternation was observed in the levels of mRNA and protein by any of the CEs in the absence or presence of PB, except for a marked decrease in the amount of mRNA when the rats were treated with 1,1-DCE in combination with PB. In the lung, both mRNA and protein were not detected under the given assay conditions, as in our previous studies. Based on these results, it is suggested that 1,1-DCE suppresses the induction of hepatic CYP2B and 2E1 in advance of the transcriptional stage. The expression of pulmonary CYP2B was obstructed by PCE posttranslationally in the absence of PB.

show abstract

Differential Modulation of CYP2E1 Activity by cAMP-Dependent Protein Kinase upon Ser129Replacement

Cited by 43 publications

References 47 publications

Maintenance of Atlantic salmon (Salmo salar) at elevated temperature inhibits cytochrome P450 aromatase activity in isolated ovarian follicles

Maintenance of Atlantic salmon (Salmo salar) at elevated temperature inhibits cytochrome P450 aromatase activity in isolated ovarian follicles

Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity

Comparative Study on the Mode of Action of Chlorinated Ethylenes on the Expression of Rat CYP Forms.

Contact Info

Product

Resources

About