Porphyrin, Hepatic

Under anaerobic conditions, p,p -DDT is converted to p,p -DDD by reductive dechlorination, a biotransfonnation that occurs postmortem in vertebrate tissues such as liver and muscle and in certain anaerobic microorganisms (Walker and Jefferies 1978). Reductive dechlorination is carried out by reduced iron porphyrins. It is carried out by cytochrome P450 of vertebrate liver microsomes when supplied with NADPH in the absence of oxygen (Walker 1969 Walker and Jefferies 1978). Reductive dechlorination by hepatic microsomal cytochrome P450 can account for the relatively rapid conversion of p,p -DDT to p,p -DDD in avian liver immediately after death, and mirrors the reductive dechlorination of other organochlorine substrates (e.g., CCI4 and halothane) under anaerobic conditions. It is uncertain to what extent, if at all, the reductive dechlorination of DDT occurs in vivo in vertebrates (Walker 1974). 

Knowledge of the biochemistry of the porphyrins and of heme is basic to understanding the varied functions of hemoproteins (see below) in the body. The porphyrias are a group of diseases caused by abnormalities in the pathway of biosynthesis of the various porphyrins. Although porphyrias are not very prevalent, physicians must be aware of them. A much more prevalent clinical condition is jaundice, due to elevation of bilirubin in the plasma. This elevation is due to overproduction of bilirubin or to failure of its excretion and is seen in numerous diseases ranging from hemolytic anemias to viral hepatitis and to cancer of the pancreas. 

All compounds caused a significant increase in EROD activity and porphyrin content in small intestine and liver, and a significant increase in hepatic P-450 content... 

PCB 105 caused significant APND induction liver had 182.0 mg PCB 105/kg FW vs. 2.4 in corn oil controls. PCB 126 induced hepatic EROD and AE liver had 3.3 mg PCB 126/kg FW. PCB 153 induced APND and AE liver contained 119.0 mg PCB 153/kg FW. For all dose groups, liver weights and liver porphyrin levels were normal... 

Decrease in weight gain moderate liver pathology gross accumulations of hepatic porphyrins and increased delta-aminolevulinic acid synthetase activity Decrease in weight gain comparatively small increase in liver weight... 

In oral studies, severe cases of porphyria (an indication of liver damage as evidenced by increased urinary excretion of porphyrins and high hepatic levels of porphyrins) were induced in male rats that... 

Miranda CL, Wang JL, Henderson MC, et al. 1984. Effects of chlorobenzenes on hepatic porphyrin and drug metabolism in chick embryo and day-old chick. Res Commun Chem Pathol Pharmacol 46 13-24. 

Wada O et ah Behavior of hepatic microsomal cytochromes after treatment of mice with drugs known to disturb porphyrin metabolism in liver. Biochem Pharmacol 17 595-603, 1968... 

Formation of S-aminolevulinic acid (ALA) All the carbon and nitrogen atoms of the porphyrin molecule are provided by two simple building blocks glycine (a nonessential amino acid) and succinyl CoA (an intermediate in the citric acid cycle). Glycine and succinyl CoA condense to form ALA in a reaction catalyzed by ALA synthase (Figure 21.3) This reaction requires pyridoxal phosphate as a coenzyme, and is the rate-controlling step in hepatic porphyrin biosynthesis. 

Definition of porphyrias, their modes of genetic inheritance, and their treatment Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. Porphyrias are classified as erythropoietic or hepatic, depending where the enzyme deficiency occurs. With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all the porphyrias are inherited as autosomal dominant disorders. All porphyrias result in a decreased synthesis of heme and, therefore, ALA synthase is dere-pressed. The severity of symptoms of the porphyrias can be diminished by intravenous injections of hemin. Because some porphyrias result in photosensitivity, avoidance of sunlight is helpful. 

Mouse (A2G-hr/+) once (GO) Hepatic 75 (3-fold increase in serum ALT, 100-fold increase in hepatic porphyrins, paracentral necrotic foci, fatty changes in midzonal region) Greig 1984,1987... 

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