title: Maternal obesity alters feto-placental cytochrome P4501A1 activity.
abstract: Cytochrome P4501A1 (CYP1A1), an important drug metabolizing enzyme, is expressed in human placenta throughout gestation as well as in fetal liver. Obesity, a chronic inflammatory condition, is known to alter CYP enzyme expression in non-placental tissues. In the present study, we test the hypothesis that maternal obesity alters the distribution of CYP1A1 activity in feto-placental unit. Placentas were collected from non-obese (BMI < 30) and obese (BMI > 30) women at term. Livers were collected from gestation day 130 fetuses of non-human primates fed either control diet or high-fat diet (HFD). Cytosol and microsomes were collected using differential centrifugation, and incubated with 7-ethoxyresorufin. The CYP1A1 specific activity (pmoles of resorufin formed/min/mg of protein) was measured at excitation/emission wavelength of 530/590 nm. Placentas of obese women had significantly reduced microsomal CYP1A1 activity compared to non-obese women (0.046 vs. 0.082; p < 0.05); however no such effect was observed on cytosolic activity. Similarly, fetal liver from HFD fed mothers had significantly reduced microsomal CYP1A1 activity (0.44 ± 0.04 vs. 0.20 ± 0.10; p < 0.05), with no significant difference in cytosolic CYP1A1 activity (control, 1.23 ± 0.20; HFD, 0.80 ± 0.40). Interestingly, multiple linear regression analyses of placental efficiency indicate cytosolic CYP1A1 activity is a main effect (5.67 ± 2.32 (β ± SEM); p = 0.022) along with BMI (-0.57 ± 0.26; p = 0.037), fetal gender (1.07 ± 0.26; p < 0.001), and maternal age (0.07 ± 0.03; p = 0.011). In summary, while maternal obesity affects microsomal CYP1A1 activity alone, cytosolic activity along with maternal BMI is an important determinant of placental efficiency. Together, these data suggest that maternal lifestyle could have a significant impact on CYP1A1 activity, and hints at a possible role for CYP1A1 in feto-placental growth and thereby well-being of fetus.
authors.affiliation: College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, OR 97239, USA. dubois@ohsu.edu
authors.forename: B N
authors.initials: BN
authors.lastname: DuBois
authors.forename: P
authors.initials: P
authors.lastname: O'Tierney-Ginn
authors.forename: J
authors.initials: J
authors.lastname: Pearson
authors.forename: J E
authors.initials: JE
authors.lastname: Friedman
authors.forename: K
authors.initials: K
authors.lastname: Thornburg
authors.forename: G
authors.initials: G
authors.lastname: Cherala
mesh_terms: D000818:Animals; D015992:Body Mass Index; D019363:Cytochrome P-450 CYP1A1 / Q000737:chemistry / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D008251:Macaca; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D009765:Obesity / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000201:enzymology* / Q000378:metabolism; D011897:Random Allocation; D012995:Solubility
chemical_list: D010078:Oxazines; C007649:ethoxyresorufin; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1