Cytochrome deficiencies

Another derepressive carbon source is melibiose, which was used in studies of mutants capable of achieving various levels of cytochrome c [37,39]. It was found that mutants low in cytochrome c are particularly sensitive with respect to glucose repression of cytochrome a. Diminished cytochrome a synthesis can, therefore, be a secondary effect of other cytochrome deficiences [37,39]. 

Chromosomal pleiotropic respiratory-deficient yeast mutants with multiple cytochrome deficiencies were first described by Sherman and SlonimskP in S, cerevisiae. Several combinations of cytochromes aa, b, c, and Cl deficiencies have been described more recently. The most common pleiotropic cytochrome deficiencies in S. cerevisiae concern both cytochromes aaz and b (strains pi, p6, p7 of ref. 85, strain plO of ref. 91, and strains S5, S6, S7, S9, S13, S19, and S20 of ref. 92). Strains 8, 16, 25, 486, 881, and El of ref. 93 might also be classified in the same class, although an additional deficiency in cytochrome Ci was reported. 

Subik et al. discovered S. cerevisiae mutants in which multiple deficiencies in cytochromes aa and b were accompanied by loss of the oligomycin sensitivity of the mitochondrial ATPase. Mutants with similar properties were reported for S. pombe. It has been suggested that in S. cerevisiae,these pleiotropic effects were the result of a deficient mitochondrial protein synthesis. Total absence of mitochondrial ATPase activity has also been reported to accompany multiple cytochrome deficiencies in S. pombe and S. cerevisiae. In the latter case, mitochondrial protein synthesis was shown to be functional. ... 

Cytochrome P450 2C19 Deficient activity in about 3% of Caucasian populations and in about 20% of Asian populations. Prolonged action of several CYP2C19 inactivated drugs like omeprazole or diazepam in the poor metabolizers. 

Cytochrome P450 2D6 Extremely high activity in about 2% of Caucasian populations and completely deficient activity in about 7%. Inefficiency in ultrarapid metabolizers and extremely heavy effects in poor metabolizers for more than 50 drugs. A few drugs requiring bioactivation by CYP have low efficacy in poor metabolizers (example codein is activated to morphine via CYP2D6). 

Fatal infantile cytochrome c oxidase (CCO) deficiency is characterized by total absence of catalytic activity in skeletal muscle. This often occurs within the context of the Fanconi syndrome, or less commonly in association with a cardiomyopathy. Although the deficiency is global in skeletal muscle, with all fibers affected, only isolated scattered fibers show abnormal aggregations of mitochondria (ragged-red fibers). Multiple affected siblings within one family are frequently encountered and suggest autosomal recessive inheritance. The condition normally proves fatal before the age of six months and is characterized by worsening intractable lactic acidemia. 

Figure 13. Mosaic of cytochrome oxidase-deficient muscle fibers (asterisks) in a patient with KSS and a heteroplasmic mtDNA deletion.

The condition known as fatal infantile mitochondrial myopathy and renal dysfunction involves severe diminution or absence of most oxidoreductases of the respiratory chain. MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) is an inherited condition due to NADHiubiquinone oxidoreductase (complex I) or cytochrome oxidase deficiency. It is caused by a muta-... 

Jaffe ER, Hultquist DE Cytochrome reductase deficiency and enzymopenic hereditary methemoglobinemia. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001. 

In vivo, patients treated with AZT develop a mitochondrial myopathy with mitochondrial DNA depletion, deficiency of cytochrome c oxidase (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion (Lewis and Dalakas 1995 Dalakas 2001). Clinically, the patient presents with fatigue, myalgia, muscle weakness, wasting and elevated serum creatine kinase. Muscle biopsy shows ragged red fibers , the characteristic histopathologic changes of mitochondrial myopathy, cansed by subsarcolemmal accumulation of mitochondria (Lewis and Dalakas 1995). 

The well-known fact that in irreversibly damaged cells, respiratory control is lost and is accompanied by oxidation of cytochromes a and as, as well as NADH (Taegtmeyer et al., 1985), was originally thoug it to be due to substrate deficiency (Chance and Williams, 1955) but may be due to an enzymatic defect resulting in an inability to metabolize NADH-linked substrates (Pelican etal., 1987). It seems likely therefore that return of function is dependent on preservation of mitochondrial membrane integrity, and the structure and activities of respiratory chain (R.C) complexes I-IV (Chance and Williams, 1955). 

Hereditary methemoglobinemia is classified into three types a red blood cell type (type I), a generalized type (type II), and a blood cell type (type HI). Enzyme deficiency of type I is limited to red blood cells, and these patients show only the diffuse, persistent, slate-gray cyanosis not associated with cardiac or pulmonary disease. In type II, the enzyme deficiency occurs in all cells, and patients of this type have a severe neurological disorder with mental retardation that predisposes them to early death. Patients with type III show symptoms similar to those of patients with type I. The precise nature of type III is not clear, but decreased enzyme activity is observed in all cells (M9). It is considered that uncomplicated hereditary methemoglobinemia without neurological involvement arises from a defect limited to the soluble cytochrome b5 reductase and that a combined deficiency of both the cytosolic and the microsomal cytochrome b5 reductase occurs in subjects with mental retardation. Up to now, three missense mutations in type I and three missense mutations, two nonsense mutations, two in-frame 3-bp deletions, and one splicing mutation in type n have been identified (M3, M8, M31). 

Sallee FR, DeVane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. 

Schuetz EG, Umbenhauer DR, Yasuda K, Brimer C, Nguyen L, Reeling MV. Altered expression of hepatic cytochromes P450 in mice deficient in one or more mdrl genes. Mol Pharmacol 2000 57 188-197. 

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