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Transport and disposition of nicotine in the human placenta

Institution: University of California, San Francisco
Investigator(s): Deanna Kroetz, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0025 Award: $333,108
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
Smoking during pregnancy is associated with many adverse outcomes on both the pregnant woman and on her fetus and newborn baby. Some of these effects include an increased chance of premature birth, a higher rate of infant death, a slower rate of fetal growth, low birth weight of the newborn, and an increased incidence of sudden infant death syndrome. Most of these adverse effects are associated with nicotine, a major component of tobacco smoke. Nicotine is also responsible for the addictive properties of this drug. With at least 16% of women continuing to smoke throughout their pregnancy, the effects of smoking on the pregnant woman and fetus are major public health concerns. This study will investigate if and how the placenta protects the fetus from nicotine. The placenta serves as a major life support organ for the fetus. Its ability to move oxygen and nutrients from maternal to fetal blood is necessary for the normal growth and development of the fetus. It also serves as a protective barrier for the fetus against harmful compounds by preventing their passage from maternal blood. Since nicotine is such a commonly used and abused drug during pregnancy, it is important to understand how the placenta functions to prevent nicotine from reaching the fetus. Specifically, this project will examine the mechanisms by which nicotine moves across cell membranes, allowing its entry both into and out of the fetus and placenta. It is likely that, once nicotine enters the placenta, it encounters “pumps” which return the nicotine back to the maternal blood, thereby protecting the fetus. We will also test whether the placenta can break down nicotine into less harmful agents. This is another possible way in which the placenta can protect the fetus from the harmful effects of nicotine (and other drugs and toxins). These studies will also determine whether the placentas of smoking women are better able to pump nicotine away from the fetus and to break nicotine down into less harmful compounds in comparison to the placentas of non-smoking women. This would mean that the placenta may have important ways in which it responds to not only nicotine but also other potentially harmful drugs as a means of protecting the fetus. Overall, these studies will greatly increase our understanding of the role of the placenta in regulating the exposure of the fetus to nicotine. This information is vitally important for us to decrease the health risks of smoking women and their newborn infants.

Final Report
Smoking during pregnancy is a major health risk for both the mother and her fetus. Nicotine is one of the major components of cigarettes and has been implicated in the adverse effects associated with smoking by pregnant women. The placenta is one potential barrier for limiting exposure of the fetus to potentially dangerous nicotine levels. We hypothesized that the conversion of nicotine to inactive byproducts (metabolism) within the placenta and the transport of nicotine across the placental membranes are the driving mechanisms which regulate nicotine levels in the fetus. The metabolic and transport capacity of the placenta will therefore be an important determinant of fetal nicotine exposure and therefore toxicity. The overall goal of the proposed studies is to understand the molecular mechanisms by which the placenta regulates nicotine levels. The objectives of these studies were 1) to characterize the transport and metabolism of nicotine in human placenta, including identification of specific drug metabolizing enzymes and transport proteins involved in these processes; and 2) to determine whether the expression of nicotine metabolizing and transport proteins is altered in the placentas from smokers relative to non-smokers.

A series of studies were carried out to identify the specific transporter proteins that can facilitate the movement of nicotine either from the placenta into the fetus or in the opposite direction. Members of the multidrug resistance family of transporters were not able to influence cellular nicotine movement but the organic cation transporters did have this activity. The organic cation transporters were found in human placental tissue and the level of this protein was not affected by the smoking status of the mother. One of the multidrug resistance transporters, MRP1, did not interact with nicotine but the expression level of this protein was significantly lower in placentas from smoking mothers compared to controls. This suggests that MRP1 might play an important role in transporting other toxic constituents of cigarettes and that downregulation prevents movement of these compounds into the fetal circulation. Metabolism of nicotine occurs at only very low levels in the human placenta and in many cases is below the limit of detection. Interestingly, we found that the use of the nicotine replacement therapy lobeline and herbal preparations containing even very low levels of lobelia were potent inhibitors of the organic cation and multidrug resistance transporters. Such inhibition could lead to significant drug interactions in smokers receiving replacement therapy.

Despite the education of pregnant women about the harmful effects of smoking on the fetus, up to 16% of these women continue to smoke throughout their pregnancy. The results from the present studies indicate that the placenta does not provide an effective barrier against fetal exposure to nicotine. Common drug metabolizing enzymes and transport proteins that are found in the placenta do not interact with nicotine. These findings have important implications for the health and viability of fetuses exposed to nicotine and support the overwhelming medical opinion that smoking cessation should be attempted as early as possible during pregnancy.

Transport and disposition of nicotine in the human placenta
Periodical: Clinical Pharmacology and Therapeutics Index Medicus:
Authors: Lacayo CI, Pak W, Benowitz NL, Tracy TS, Kroetz DL ABS
Yr: 2001 Vol: 69 Nbr: Abs: Pg: P95

Metabolism of nicotie in pregnant rabbits.
Periodical: Clinical Pharmacology and Therapeutics Index Medicus:
Authors: Tutka P, Dempsey DA, Benowitz NL, and Kroetz DL ABS
Yr: 2000 Vol: 67 Nbr: Abs: Pg: 132