CYP Guidelines

ABBREVIATIONS: GENERAL NOTES [2003-11-24]

Name + (Abbreviation)

Often we see a long name followed by an abbreviation in parentheses, or after a dash. If the name refers to a kind of entity that is being tagged in your domain, tag the name and the abbreviation, separately. They are two names for the same entity. Don't tag the parentheses:

monoclonal gammopathy of undetermined significance (MGUS)

[2003-12-11] When considering how much of a long name to tag, take the abbreviation into account. The fact that the authors used an abbreviation for a phrase, even if they invented it, is very strong motivation to tag the whole phrase that it stands for, even if it includes modifiers or other terms that we would otherwise exclude. For example:

The selective serotonin reuptake inhibitors (SSRIs)--paroxetine, sertraline, and fluvoxamine--have elimination half-lives of 15-26 hours.

Depending on domain-specific guidelines, a modifier such as "selective" might normally be excluded from the tagged string. But here it is obviously part of the phrase, represented by the first "S" in "SSRIs". That's sufficient reason to consider "selective" part of the full name of the entity.

Name + (Abbreviation) + More Name

But sometimes such a name+abbreviation is part of a longer name, which continues on after the parenthesized abbreviation. In such cases we do not try to separate out the abbreviation; that would make a tag within tag situation, which we try to avoid. So we just tag the longer name:

P-glycoprotein (P-gp)-related compounds

CHAINS *

Coordination in split references: [2005-01-26]

We chain only for conjunctive constructions, i.e., where the text uses "and" or "or" (or another word, or punctuation, used similarly) to join two or more similar elements, and some or all of the elements share a part. (In our documentation we use "(+)" to separate the links of a chain.)

1. androgen and estrogen receptors
   The shared element, "receptors", is on the right of the conjoined section.

   • "androgen  (+)  receptors": tag as a chain
   • "estrogen receptors": single string

2. organic acids and salts
   Here the shared element is on the left.

   • "organic acids": single string
   • "organic  (+)  salts": chain

3. P450IA1 or IA2   =   "P450IA1 or P450IA2"
   The links of the chain are not complete tokens. You will need to adjust the tokenization to split "P450IA1" into "P450" and "IA1" so you can chain "P450" with "IA2".

   • "P450IA1": single string
   • "P450  (+)  IA2": chain

4. CYP1A1/2   =   "CYP1A1 or CYP1A2"
   Like the previous example but with a slash instead of "or".

   • "CYP1A1": tag as a string
   • "CYP1A  (+)  2": tag as a chain

5. H-, K-, and N-ras
   Three conjoined elements, but the principle is the same as #3, splitting "N-ras" into two tokens. Be sure to capture the hyphens (but only one per chain): capture "H-ras", not "Hras" or "H--ras".

   • "H-  (+)  ras": chain (or "H  (+)  -ras")
   • "K-  (+)  ras": chain (likewise)
   • "N-ras": single string

6. organic and inorganic acids and salts
   Two shared elements, one on each end! Fortunately, this sort of thing is rare.

   • "organic   (+)  acids": chain
   • "organic  (+)  salts": chain
   • "inorganic acids": single string
   • "inorganic  (+)  salts": chain

Note: WordFreak will allow you to make a chain with some links in one sentence and some in another. It shouldn't allow this, in the same way as we don't allow (and WF doesn't allow) any single solid tag to span more than one sentence. So do NOT use the chaining tool to make chains across sentences.

Complex Chains:

Some chaining situations can be even more complex:

cytochrome P450 11 beta/18/19 -hydroxylase

Here we would have 3 chains:

1. cytochrome P450 11 beta  (+)  -hydroxylase
2. cytochrome P450  (+)  18  (+)  -hydroxylase
3. cytochrome P450  (+)  19 -hydroxylase

Chains with embedded abbreviations:

When abbreviations are embedded in a split coordination, we do not skip the abbreviated part during chaining. The abbreviated part is included in the chain as per existing abbreviation rules.

cytochromes P450 (CYP) 1A1, 1A2, and 1B1

1. cytochromes P450 (CYP) 1A1 [single tag]
2. cytochromes P450 (CYP)  (+)  1A2 [chain]
3. cytochromes P450 (CYP)  (+)  1B1 [chain]

CYTOCHROME P450

We will tag the names of cytochrome P450 enzymes as such when they occur in the text. The purpose of this annotation is to supply machine learning algorithms with enough information about the variant spellings of the enzyme, e.g., CYP450, CYP4503a, P450, etc.

A quantitative assessment of the levels of cytochromes P-450 b and P-450 c in....
                                           -----------             -------

Tag "cytochromes P-450 b" as CYP. Chain "cytochromes (+) P-450 c" and tag it also as CYP. *

Isozyme/Isoform and abbreviated CYP entities:

Often "cytochrome P450" is accompanied by the word "isozyme" or "isoform". Isozymes are any of two or more chemically distinct but functionally similar enzymes. We tag the entire string as CYP:

cytochrome P450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8)

1. "cytochrome P450 (CYP) 4A isoforms" is one entity, tagged as CYP. If it were just "cytochrome P450 (CYP)" we would tag two strings, "cytochrome P450" and the parenthesized "CYP" (but not the parentheses), as standard procedure for "NAME (ABBREVIATION)". But since the parenthesized abbreviation is embedded in a longer name, we don't try to extract it. See rule.

2. "4A1", "4A2", "4A3", and "4A8" are all separate references, each tagged as CYP. So there are five strings to tag here, all as CYP; and no chaining is required:
   • cytochrome P450 (CYP) 4A isoforms
   • 4A1
   • 4A2
   • 4A3
   • 4A8

Pseudo CYPs:

Often you will find entity references which have "cyp 450" embedded within them. These entities might look like CYPs but are actually complexes and hence tagged as Substance.

• Cytochrome P-450 Oxidase
• Cytochrome P-450 Reductase
• Ferrihemoprotein P-450 Reductase
• NADPH Cytochrome P-450 Oxidoreductase
• NADPH Cytochrome P-450 Reductase
• NADPH Cytochrome P450 Reductase
• NADPH-P450 Reductase
• NADPH Cytochrome c Reductase
• NADPH-specific cytochrome c reductase

THESE ARE SUBSTANCES, NOT CYPs. In all of these cases, "cyp 450" (or equivalent) is part of a modifier of the last word in the expression, and the last word is the kind of thing referred to. This is standard in English. For example,

• a ham sandwich is a sandwich, not a ham
• a government document is a document, not a government
• a metal salt is a salt, not a metal

Not surprisingly, many of the names on the above list are synonyms. Here is a refreshingly clear [to a layman like me -- M.A.Mandel] explanation of what NADPH-cytochrome P450 reductase is, why its name includes "P450", and why it isn't a CYP450 enzyme. [2005-01-26]

Non-obvious CYP enzymes:

Many CYP450 enzymes are known by a number of names that don't include "cyp" or "450".

1. The compounds were all shown to exhibit weak inhibitory activity against rat testes P450 17 (17,20-lyase), indicating good selectivity towards P450arom.

   There are 3 CYP tags in this sentence:

   • "P450 17" is a CYP
   • "17,20-lyase" is tagged as CYP even though it is not in the CYPxxx format. You will find it in the CYP synonyms list.
   • "P450 arom" is a CYP

2. "Cholesterol 7 alpha-hydroxylase" is a synonym for CYP 7

3. "Cholesterol side chain cleavage" is a cytochrome P450 enzyme, also called "P450scc".

To help you keep track of these, we have a synonyms page, which includes some discussion of non-obvious synonyms and of non-obvious non-synonyms (terms that look like CYP450 names but aren't). Whenever you spot a new member of one of these categories, please post it to the mailing list. Note: It is important to validate a nonobvious CYP enzyme. Some of these reference tools can prove useful.
(01/04, [2004-08-10])

Local Co-reference:

When an entity refers to a CYP and the entity is in the SAME SENTENCE as the CYP, then that entity should be tagged as CYP. Else it should be tagged as substance and the CYP name should be mentioned in the comment field.

1. We investigated the effect of the steroid hormone dehydroepiandrosterone (DHEA) on the hepatic expression and activity of carcinogen-activating enzymes, the cytochromes P450 (CYP) 1A1, 1A2 and 1B1, in Sprague-Dawley rats.

   Here "carcinogen-activating enzymes" refers to a list of CYP enzymes and is in the same sentence as the CYP enzymes. Hence it should be tagged as CYP. The enzyme names should be treated as above:

   • cytochromes P450 (CYP) 1A1 - single string
   • cytochromes P450 (CYP) (+) 1A2 - chain
   • cytochromes P450 (CYP) (+) 1B1 - chain

   On the other hand, the same phrase occurs in the title of the abstract:

   Dehydroepiandrosterone inhibits the expression of carcinogen-activating enzymes in vivo.

   Here "carcinogen-activating enzymes" is tagged as Substance, because it does not refer to any CYP enzymes in the same sentence.

2. CYP 4A plays an important role in metabolizing drug arbitor. This enzyme also...

   Again the word "enzyme" is tagged as Substance since the CYP it is referring to (CYP 4A) is not in the same sentence. Comment: CYP 4A
   

   (02/04)

SUBSTANCE

Some generalizations [2004-09-22]

This list of some kinds of terms that we tag as Substance is based on the original list that came out of the ChemFest meeting held on 2003-04-03, before annotation began in this project.

• DNA
• receptor (see solid)
• "venom, toxin", etc.
• foods and beverages, e.g.,
  • grapefruit juice
  • red wine
  • whole grains
  • legumes
  • fruits
  • vegetables
• names of drugs and the word "drug" and similar words, such as "antibiotic"
• residue (including "amino acid residue"; see solid)
• "metabolite, precursor", etc. (see solid)
• element names
• ions: "K(+)" is one of the ways they're symbolized. Not to be confused with measurements.

Genes vs. Proteins

Very commonly a gene and a protein are called by the same name. The oncology annotators tag both genes and proteins, distinguishing them where possible, but in CYP we tag proteins as substances and we don't tag genes at all.

1. "the K-ras gene" - no tag because CYP doesn't tag genes
2. "the K-ras protein" - tag the phrase, "K-ras protein", with the Substance label. You need to include the word "protein" to make it clear that this reference is to a Substance.

Organs, Species, Cells, etc.:

We do not tag organ names, body parts, species, micro-organisms, cell types, tissues, plasma, blood etc as substance. We are mainly interested in the names of enzymes, drugs, organic molecules and other chemicals and we tag these as Substance.

1. gastric proton pump  inhibitor

   "Gastric" here means of or relating to the stomach. So we do NOT tag "gastric". But we tag "proton pump" as Substance and "inhibitor" separately as a Substance. See Split vs. solid.

2. "human cytochrome P450 enzyme"

   Again we do not tag "human". "cytochrome P450 enzyme" is tagged as CYP.

Note: We have established two exceptions to this rule. Like much else in this project, it is subject to reconsideration as new situations arise. If in doubt, ask.

• Abbreviated exception
• Quant Units exception

Parts of a molecule or site name:

A part or chunk of a molecule, such as a region, a site, a radical, or a single atom, is not a "chemical", and therefore not a "Substance", unless it's out there on its own, no longer part of what it used to belong to. For example:

• The ability of aminoglutethimide to inhibit cholesterol conversion to pregnenolone was lost upon acetylation of the arylamine nitrogen.
  Here "the arylamine nitrogen" is a part of aminoglutethimide: the nitrogen atom in the arylamine ring of aminoglutethimide. Since it is part of a molecule (aminoglutethimide), we don't tag any part of this phrase.

• substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3'-position of the phenol ring...
  A moiety is a portion of a molecule, and the benzothiophene moiety is the portion that contains a benzothiophene; again, no part of this expression should be tagged as a Substance. [2004-11-18]

But in general how do we know? The use of "the" and a specifying term ("the XXX nitrogen") is a clue that the author is referring to a specific nitrogen atom in the molecular structure, not to the substance nitrogen.

This does require some domain knowledge, but these clues should help. If you're fairly sure that a reference like this is to a particular part of a molecule rather than to a substance, don't tag it. But don't break your head trying to figure out such a situation. If it looks like a substance and you can't figure out fairly quickly whether this test applies, go ahead and tag it.
(07/03)

Substance modifiers:

Often you will encounter substance names with different types of modifiers either preceding the substance name or following it. Some of them have been listed here.

1. Origin modifiers:

   These are modifiers that provide information about the origin of a substance. We do NOT tag such modifiers.

   Different natural and synthetic organic hydroperoxides have been found to stimulate TBARS formation in human term placental mitochondria.

   There are two modified substance terms here:

   • natural organic hydroperoxides
   • synthetic organic hydroperoxides

   If we tagged them, the first would be a chain and the second a single string. But in both cases we tag only "organic hydroperoxides"; and since it occurs only once here, we tag it only once. "Organic" describes the composition of the substance ("inorganic" would qualify in the same way). But "synthetic" and "natural" tell about the origin of it; exclude them.
   (04-04-25)

2. Process modifiers:

   These are modifiers that give information about the procedures or processes performed on the substance. We do NOT tag them.

   Immature rat Sertoli cells synthesize and secrete a protein species which has immunological similarity with chicken egg thiamin carrier protein (TCP) as assessed by immunocytochemical localization, liquid phase radioimmunoassay (RIA), immunoprecipitation of [35S]-methionine incorporated newly synthesized proteins by polyclonal antibodies (pAbs) to chicken TCP and tryptic peptide mapping of iodinated immunoprecipitated proteins.

   • iodinated immunoprecipitated proteins

     Tag "proteins" as a substance and do not tag "iodinated" and "immunoprecipitated". Iodination and immunoprecipitation are laboratory techniques and hence will not be tagged.

   • tryptic peptide

     Only tag "peptides"as a substance. This is because [tryptic (peptide mapping)] is a process of peptide mapping which is done in a tryptic way, where tryptic means 'relating to trypsin or to its action'.

   (10/03)

General substance names:

If the general word is not part of a more specific phrase then

I. If it refers in context to a specific entity or group of entities (not necessarily a small group) - Tag it. *

II. If it's completely general and refers to all the things of its kind - Don't tag.

1. We have investigated whether pyrene, a major compound of ....
   Tag "compound" as Substance. (Also tag "pyrene" itself as Substance.) *
   

2. The six compounds tested are ICR 191, 170, 292, 372, 191-OH, and 170-OH.
   Tag "compounds" as Substance, with the comment "ICR 191, 170, 292, 372, 191-OH and 170-OH" -- or, for brevity, "ICR 191, ... 170-OH" would be enough. (Also tag the individual compound names as Substance, which will require chaining to join the last five of them with "ICR".)

3. This phenomenon has been reported only once previously and, despite its potential clinical importance, nitromethane does not appear in published lists of substances that interfere with the Jaffe reaction.
   Here "substances" is very general and hence should not be tagged.

Substance name embedded in procedure name:

Substance names may also appear as part of a procedure name or lab technique. In such cases we just go ahead and tag the Substance name.

1. "DNA analysis" - tag "DNA" as Substance
2. "RNA-assay methods" - tag "RNA" as Substance
3. "enzyme-linked immunosorbent assay (ELISA)" - tag "enzyme" as Substance

Complexes:

On many occasions, substances exist as complexes. In such situations, do not try to tag each Substance within the complex separately. Rather tag the entire complex as one string.

1. "orphenadrine complex": Tag the whole thing as one Substance.
2. "orphenadrine metabolite complex": Same as above.
3. "NADPH-Cytochrome c Reductase" is tagged together and NOT "NADPH" and "cytochrome c Reductase" separately.

Tag each of these expressions, and in general "XYZ complex", as a single substance.

Abbreviations:

General abbreviation rules can be found here.

Abbreviations vs. Quant Name:

Sometimes abbreviations can be confused with quant name.

The EDHF-mediated dilations initiated by ACh and histamine, as well as K(ATP) activation by cromakalim, were blocked by mepacrine, a nonselective phospholipase A2 inhibitor. Mepacrine did not alter K(Ca) activation by compound NS-1619.

Here "K(ATP)" and "K(Ca)" might be confused with "K(i)", which is an inhibition constant and hence a quant name. But "K(ATP)" and "K(Ca)" are not related to "K(i)".

• "K(ATP)": ATP-sensitive potassium channel
• "K(Ca)": Calcium-sensitive potassium channel

Abbreviations that help:

Sometimes abbreviations are helpful in making a decision as to whether a particular phrase should be tagged as a substance or not. See the discussion in the General Guidelines for Entity Annotation.

1. flavin-containing mono-oxygenase form 3 (FMO3)

   Something like this long term could go either way if it didn't have the abbreviation after it. It might be a name, or it might be just a description. But the abbreviation clinches it: it tells us that, at least in this text, "flavin-containing mono-oxygenase form 3" is functioning as a name. So we tag it as a Substance, and we tag the abbreviation as well.

2. The objective of the current study was to monitor the effects of cotinine and cigarette smoke (CS) on the formation of O6MeG in target tissues of mice during the acute phase of NNK treatment.

   Here "cigarette smoke" is a Substance, as validated by the abbreviation "CS". Tag them both as Substance.

3. Characterization and hormonal modulation of immunoreactive thiamin carrier protein (TCP) in immature rat Sertoli cells in culture.

   We will only tag "thiamin carrier protein" as a Substance and not tag "immunoreactive". This is because "thiamin carrier protein" occurs symbolically in the abstract as "TCP".
   (11/03)

Although we generally do not tag organ names, body parts, species, cell types, etc., if any of these appear as part of the abbreviated form, we include it in the tagged text.

1. human placental lactogen (HPL)

   Here we see that lactogen is the substance of interest. We usually would not tag "human" or "placental". But the abbreviated form HPL tells us that the entire string is treated together as a name. So we tag "human placental lactogen" and its abbreviation "HPL" each as Substance.

2. human chorionic gonadotropin (hCG)

   Similarly tag "human chorionic gonadotropin" and "hCG" as Substance.

Symbols vs. Abbreviations:

When abbreviations of Substance names are reduced to symbols, we generally do not tag these symbols.

    (Polyclonal/Monoclonal) {host name} anti-{antigen name} Ig{Immune globulin type}

     polyclonal goat anti-human tpA IgG
                host       antigen    type
               =goat    = human tpA   = G

     nanomoles
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 minute · milligram