**10. Possible sources of metal ion supply**

#### **10.1. ATP-metabolism and heavy metal ion interactions**

Pb, Cd and Ag has higher association to binding sites than Mg, Ca. Possible effect is displace‐ ment of Mg from enolase enzyme which introduces a double bond in the phosphate group. Mg may also be blocked in the phospho-mutase reaction when phosphoglycerate is transferred from position 3 to position 2. Another effect of cadmium ions is inhibition of Na/K ATPase enzyme by 50% in ABC-transporters (Lijnen et. al. 1991). Examples above indicate possible effects of heavy metal ions in the ATP-metabolism.

#### **10.2. Pb, Ag, Cd interactions with dopamine metabolism**

In patients with Parkinon's disease the micoenvironment is full of misfolded alfa-Synuclein (George et.al. 2013) in brain (striatum) which may promote aggregation of cells and cause losses in dopamine synthesis. The synthesis in substantia nigria may be blocked by the increased concentrations of Pb, Ag and Ag. Transport of compounds (dopamine, acetylcholine) by vesicles (Kornberg and McConnell, 1971) in axons may be blocked by reactions with heavy metal ions.

#### **10.3. Axonal transport and membrane trafficking**

The axonal transport of mitochondria (Hollenbeck and Saxton, 2006, Gunter et.al 2000) may be disturbed by Pb, Cd and Ag by carry over effects. Mitochondria were transported by kinosin, dynein and myosin motors (Zhang and Zhao, 2007). Interactions with the motor transport in axons may be expected to slow down or stop movements when exposed to Pb, Ag and Cd. The transport of Ca (Perin et.al.1990) may be blocked by Pb, Cd and due to stronger association to binding sites in the mitochondria and ER (endoplasmatic reticulum) resulting in poor nerve signals in the axons.

#### **10.4. ROS formation by increased activity of hemeoxidases and displaced iron**

The accumulated heavy metal ions in the erythrocytes may disturb oxygen transport and interact with important brain cells. Cd may be used in heme metabolism, reducing heme concentration when sufficient. In a previous study significantly increased concentration of Cd was observed in the erythrocytes (Johansson et.al. 2007). The gene for hemeoxygenases HO-1, HO-2 is Cd dependent (Koizumi et.al.2007, Alami et.al.2000). HO-1, HO-2 hemeoxygenases are important for cleaning up residues of senescent erythrocytes. Low concentrations of Cd may be involved in cleaning up heme residues, too high concentration of Cd may support formation of reactive oxygen species (ROS), superoxide anion, hydroxy free radicals, and singlet oxygen. In the porphyrine synthesis it is important that introduction of iron (ferroche‐ latase, frataxin) is not blocked by excess Cd, Pb, Ag (Johansson et.al. 2007). Uncontrolled iron may react with oxygen and produce free radicals, Haber-Weiss reactions.

#### **10.5. Preapoptosis signals and possible activation of second messengers**

Cd may enter Ca channels (e.g. Gardos channels) in the erythrocyte membrane and introduce interactions in cells (Verbost et.al.1989). Cd, Pb, Ag may release Ca from calmodulin (super‐ family of Ca-carriers) due to weaker binding. Ca Is an important secondary messengers in cells activating e.g. flippases. Liberated Ca may activate translocators, flippases, within the cell (Devaux et.al. 2006). Phosphatidylserine in the inner leaflet may be transferred by trans locators to outer membrane giving an apoptosis marker for the macrophages. Phosphatidyl‐ serine is normally situated below leflet (Martin et.al. 1995). Increased Pb, Cd, Ag may start too early apoptosis of important cells e.g. neurons (Sopjani et.al.2009).

#### **10.6. Pb and porphyrine synthesis**

of Cd (9/12) was also higher than that of controls. The observed increased of concentrations of Pb, Ag and Cd may have effects at different levels, e.g. 1. ATP-metabolism and heavy metal ion metabolism 2. Pb, Ag, Cd interactions with dopamine metabolism 3. Axonal transport and membrane trafficking 4. ROS formation by increased activity of hemeoxidases and displaced iron 5. Preapoptosis signals and possible activation of second messengers 6. Pb and porphyrine

Pb, Cd and Ag has higher association to binding sites than Mg, Ca. Possible effect is displace‐ ment of Mg from enolase enzyme which introduces a double bond in the phosphate group. Mg may also be blocked in the phospho-mutase reaction when phosphoglycerate is transferred from position 3 to position 2. Another effect of cadmium ions is inhibition of Na/K ATPase enzyme by 50% in ABC-transporters (Lijnen et. al. 1991). Examples above indicate possible

In patients with Parkinon's disease the micoenvironment is full of misfolded alfa-Synuclein (George et.al. 2013) in brain (striatum) which may promote aggregation of cells and cause losses in dopamine synthesis. The synthesis in substantia nigria may be blocked by the increased concentrations of Pb, Ag and Ag. Transport of compounds (dopamine, acetylcholine) by vesicles (Kornberg and McConnell, 1971) in axons may be blocked by reactions with heavy

The axonal transport of mitochondria (Hollenbeck and Saxton, 2006, Gunter et.al 2000) may be disturbed by Pb, Cd and Ag by carry over effects. Mitochondria were transported by kinosin, dynein and myosin motors (Zhang and Zhao, 2007). Interactions with the motor transport in axons may be expected to slow down or stop movements when exposed to Pb, Ag and Cd. The transport of Ca (Perin et.al.1990) may be blocked by Pb, Cd and due to stronger association to binding sites in the mitochondria and ER (endoplasmatic reticulum) resulting

The accumulated heavy metal ions in the erythrocytes may disturb oxygen transport and interact with important brain cells. Cd may be used in heme metabolism, reducing heme concentration when sufficient. In a previous study significantly increased concentration of Cd was observed in the erythrocytes (Johansson et.al. 2007). The gene for hemeoxygenases HO-1, HO-2 is Cd dependent (Koizumi et.al.2007, Alami et.al.2000). HO-1, HO-2 hemeoxygenases

**10.4. ROS formation by increased activity of hemeoxidases and displaced iron**

synthesis

metal ions.

**10. Possible sources of metal ion supply**

396 Pharmacology and Nutritional Intervention in the Treatment of Disease

effects of heavy metal ions in the ATP-metabolism.

**10.3. Axonal transport and membrane trafficking**

in poor nerve signals in the axons.

**10.2. Pb, Ag, Cd interactions with dopamine metabolism**

**10.1. ATP-metabolism and heavy metal ion interactions**

Pb is not known to be essential to man. Pb has redox capacity (Pb2+or Pb4+) and usually associated in reduced form to other molecules. As about 99% of Pb is associated to erythrocytes in blood one target will be the metabolism of erythrocytes. Pb is known to interfere with aminolevulinic acid dehydratase in the heme synthesis (Flindt et.al. 1976, Kelada et.al.2001). Pb is also known to interact with Ca channels by allowing increased input of calcium starting too early senescence (Lang et.al. 2010).

#### **10.7. Possible sources of metal ion supply**

In the study of 12 Parkinson patients (Johansson et.al.2013) there was no information of food habits for individual patients. In Finland cadmium uptake from food is about 5-10 µg/day, lead 20-66 µg /day, silver was not mentioned. In Sweden cadmium uptake from wheat, rice, potatoes, root-crops is about 10-20 µg /day, lead 15-30 µg /day, silver was not reported. In view of contribution from nutrition of heavy metal ions it is interesting to note that cadmium rich diet in Nigeria decreased Hb and erythrocyte counts in mice (Asagba & Eriyamremu 2007). It cannot be excluded that cadmium, lead in food after long time may accumulate in human erythrocytes and likely decrease erythrocyte counts and hemoglobin synthesis. Smoker may have higher cadmium values in blood but there was no information about smoking habits. Implanters may be a source of metal ion supply. Amalgam is an alloy which is not stable but will release mercury, silver (Johansson E1991, Johansson E et.al.1994, Johansson E and Liljefors T, 1991). Studies indicate that released mercury from amalgam will be found in liver, kidney and brain only minor amounts of mercury will be found in the blood indicating need for looking after other indicators. The effects of silver are often missing but should be included due to effects of silver on important antioxidant compounds containing selenium, sulphur. Some amalgam fillings may have small sticks of guttapercha in the cavity. Some trademarks of Gutta-percha contain cadmium but the released amount is not known for the examined patients (Johansson E and Liljefors T 1991).The observations of problems possibly attributed to implanters should be considered in the early diagnosis.

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#### **10.8. The discoid shape of erythrocytes and heavy metal ions**

Erythrocytes must be able to shrink and expand during transport (Huang et.al. 2010). If Cd, Pb, Ag, are associated to stabilizing proteins, erythrocytes possess a spectrin-based cytoske‐ leton they may lose their capacity to shrink and expand (Zhang and Zhao, 2007, Bosman et.al. 2008) in the capillaries.
