Cytochrome P450 oxidase

Physiology

See Also

• Genetic polymorphisms in dietary xenobiotic metabolizing enzymes
• [Phase I metabolism]?
• [Phase II metabolism]?
• [Drug metabolism]?

Description

Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1.14) important in animal physiology. The cytochrome P450 mixed-function monooxygenase system is probably the most important element of Phase I metabolism in animals (metabolism in this context being the chemical modification or degradation of chemicals including drugs and endogenous compounds).

Cytochrome P450 sequence homologs have been determined in all lineages of life, including mammals, birds, fish, insects, worms, sea squirts, sea urchins, plants, fungi, slime molds, bacteria and archaea.

P450s are membrane-associated proteins, either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells where they metabolise thousands of endogenous and exogenous compounds. In the liver, these substrates include drugs and toxic compounds as well as metabolic products such as bilirubin (a breakdown product of hemoglobin). Cytochromes P450 are present in many other tissues of the body including the mucosa of the gastrointestinal tract, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. In most animals, including humans, hepatic cytochromes P450 are the most widely studied of the P450 enzymes.

The name refers to "pigment at 450 nm", so named for the characteristic Soret peak formed by absorbance of light at wavelengths near 450 nm when the heme iron is reduced (with sodium dithionite) and complexed to carbon monoxide.

Molecular biology

Mammalian cytochrome P450 oxidases have about 500 amino acids and a heme (h�m) group at the active site. Most can metabolize multiple substrates, and many can catalyze multiple reactions, which accounts for their central importance in metabolizing the potentially endless variety of endogenous and exogenous molecules. Most animal cytochromes P450 have a cofactor cytochrome P450 reductase and require the nucleoside cofactor NADPH and molecular oxygen (O2) to function.

The Human Genome Project has identified 63 human genes (57 full genes and 5 pseudogenes) coding for the various cytochrome P450 enzymes [1].

Nomenclature

Genes encoding for the P450 enzymes, and the enzymes themselves, are designated with the abbreviation CYP, followed by an Arabic numeral indicating the gene family, a capital letter indicating the subfamily, and another numerals for the individual gene. The convention is to italicise when referring to the gene. For example, CYP2E1 is the gene that encodes for the enzyme CYP2E1 � one of the enzymes involved in paracetamol (acetaminophen) metabolism. There is a Nomenclature Committee that keeps track of and assigns new names.

CYP Families in humans

Humans have 18 families of cytochrome P450 genes and 43 subfamilies (Nelson, 2003):

• CYP1: drug and steroid (especially estrogen) metabolism (3 subfamilies, 3 genes, 1 pseudogene)
  • CYP1A1, CYP1A2, CYP1B1, CYP1A8P (pseudogene)
• CYP2: drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes)
  • CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2B7, CYP2C8, CYP2C9, CYP2C11, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2G1P (pseudogene), CYP2G2P (pseudogene), CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1
• CYP3: drug and steroid (including testosterone) metabolism (1 subfamily, 4 genes, 2 pseudogenes)
  • CYP3A4, CYP3A5, CYP3A7, CYP3A43
• CYP4: arachidonic acid or fatty acid metabolism (6 subfamilies, 11 genes, 10 pseudogenes)
  • CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4V2, CYP4X1, CYP4Z1
• CYP5: thromboxane A2 synthase (1 subfamily, 1 gene)
  • CYP5A1
• CYP7: bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (2 subfamilies, 2 genes)
  • CYP7A1, CYP7B1
• CYP8 (2 subfamilies, 2 genes)
  • CYP8A1 (prostacyclin synthase), CYP8B1 (bile acid biosynthesis)
• CYP11: steroid biosynthesis (2 subfamilies, 3 genes)
  • CYP11A1, CYP11B1, CYP11B2
• CYP17: steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase
  • CYP17A1
• CYP19: steroid biosynthesis (1 subfamily, 1 gene): aromatase synthesizes estrogen
  • CYP19A1
• CYP20: unknown function (1 subfamily, 1 gene)
  • CYP20A1
• CYP21: steroid biosynthesis (2 subfamilies, 2 genes, 1 pseudogene)
  • CYP21A2
• CYP24: vitamin D degradation (1 subfamily, 1 gene)
  • CYP24A1
• CYP26: retinoic acid hydroxylase (3 subfamilies, 3 genes)
  • CYP26A1, CYP26B1, CYP26C1
• CYP27: (3 subfamilies, 3 genes)
  • CYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3), CYP27C1 (unknown function)
• CYP39: 7-alpha hydroxylation of 24-hydroxycholesterol (1 subfamily, 1 gene)
  • CYP39A1
• CYP46: cholesterol 24-hydroxylase (1 subfamily, 1 gene)
  • CYP46A1
• CYP51: cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes)
  • CYP51A1 (lanosterol 14-alpha demethylase)

Other specific CYP functions in humans

A subset of cytochrome P450 enzymes play important roles in the synthesis of steroid hormones by the adrenals, gonads, and peripheral tissue:

• CYP11A1 (also known as P450scc or P450c11a1) in adrenal mitochondria effects �the activity formerly known as 20,22-desmolase� (20α-hydroxylase, 22-hydroxylase, cholesterol side chain scission).
• P450c11β in inner mitochondrial membrane of adrenal cortex conducts 11β-hydroxylase, 18-hydroxylase, 18-methyloxidase activities.
• P450c11AS, only in mitochondria of the adrenal zona glomerulosa conducts 11β-hydroxylase, 18-hydroxylase, 18-methyloxidase activities.
• CYP17A1 (P450c17), in endoplasmic reticulum of adrenal cortex conducts 17α-hydroxylase and 17,20-lyase activities.
• CYP21A1 (P450c21) in adrenal cortex conducts 21-hydroxylase activity.
• CYP19A (P450arom, aromatase) in endoplasmic reticulum of gonads, brain, adipose tissue, and elsewhere catalyzes aromatization of androgens to estrogens.
• CYP102 (also known as P450BM3) monooxygenation of C15 and C16 fatty acid chains.

Links

Attribution

• This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Cytochrome P450.